KR20230072446A - Synergic combination of 2,3-dioxygenase inhibitor and immune checkpoint inhibitor for the treatment of cancer - Google Patents
Synergic combination of 2,3-dioxygenase inhibitor and immune checkpoint inhibitor for the treatment of cancer Download PDFInfo
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- KR20230072446A KR20230072446A KR1020220153645A KR20220153645A KR20230072446A KR 20230072446 A KR20230072446 A KR 20230072446A KR 1020220153645 A KR1020220153645 A KR 1020220153645A KR 20220153645 A KR20220153645 A KR 20220153645A KR 20230072446 A KR20230072446 A KR 20230072446A
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- cyclohexyl
- fluoroquinolin
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Abstract
Description
본 발명은 암 치료에 유용한 인돌아민 2,3-디옥시게나아제 저해제와 면역체크포인트 억제제의 상승적 조합에 관한 것이다. 더욱 상세하게는, 본 발명은 인돌아민 2,3-디옥시게나아제 1(indoleamine 2,3-dioxygenase 1, IDO1)의 선택적 억제제와 면역체크포인트 억제제, 특히 PD-1/PD-L1 신호전달 억제제, 예를 들어 프로그램화된 사멸 1 단백질(PD-1) 길항제의 암의 치료를 위한 상승적 조합(synergic combination)에 관한 것이다.The present invention relates to synergistic combinations of indoleamine 2,3-dioxygenase inhibitors and immune checkpoint inhibitors useful in the treatment of cancer. More specifically, the present invention provides a selective inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1) and an immune checkpoint inhibitor, particularly a PD-1/PD-L1 signaling inhibitor, For example, it relates to synergic combinations of programmed
비소세포성 폐암(non-small cell lung cancer, NSCLC)를 포함한 몇몇 종양은 면역계의 공격으로부터 회피하기 위한 방어 메커니즘으로 종양 미세환경을 변화시켜 면역기능을 억제하거나, T 세포 면역관용(immunetolerance) 또는 면역편집(immuno-editing) 등을 통하여 면역회피(immune escape)를 하려 한다. 면역체크포인트는 암세포 파괴를 방해하는 단백질로서, 암은 면역 억제 분자들을 활성화시켜 T 세포의 공격을 회피하는 종양 내성을 갖게 된다. 대표적으로 암세포에 PD-L1 이라는 특정 세포 표면 단백질이 발현될 경우, T 세포에 존재하는 PD-1과 결합하여 T 세포 기능을 억제하여 면역을 회피한다.Some tumors, including non-small cell lung cancer (NSCLC), suppress immune function by altering the tumor microenvironment as a defense mechanism to evade attack by the immune system, or develop T-cell immunotolerance or immunity. Immune escape is attempted through immuno-editing, etc. Immune checkpoints are proteins that interfere with the destruction of cancer cells, and cancers become tumor resistant by activating immune suppressive molecules to evade T cell attack. Typically, when a specific cell surface protein called PD-L1 is expressed in cancer cells, it binds to PD-1 present in T cells to suppress T cell functions and evade immunity.
면역체크포인트 억제제는 암을 공격하는 T 세포의 활성을 제어하는 면역체크포인트 수용체(CTLA-4, PD-1)에 직접 결합하거나, 암 세포 표면에 있는 PD-L1에 결합하여 면역회피 신호를 차단함으로써 면역학적 시냅스가 형성되지 못하게 하고, 이에 따라 면역회피 방해를 받지 않는 T 세포가 암세포를 파괴하는 기전을 가지고 있다. 대표적인 면역체크포인트 억제제로는 CTLA-4 모노클로날 항체[예를 들어, Ipilimumab (YERVOYTM) 등], PD-1 모노클로날 항체[Nivolumab (OpdivoTM), Pembrolizumab (KeytrudaTM) 등], PD-L1 모노클로날 항체[Atezolizumab (TECENTRIQTM), Durvalumab (IMFINZITM) 등]이 알려져 있다. 그러나, 여전히 면역체크포인트 억제제는 전체의 암 환자군 중 일부에게만 성공적으로 반응하며, 자가면역질환 등의 부작용 극복이 필요한 것으로 알려져 있다. Immune checkpoint inhibitors block immune evasion signals by directly binding to immune checkpoint receptors (CTLA-4, PD-1) that control the activity of T cells that attack cancer, or by binding to PD-L1 on the surface of cancer cells. By doing so, the formation of immunological synapses is prevented, and thus T cells that are not interfered with immune evasion have a mechanism to destroy cancer cells. Representative immune checkpoint inhibitors include CTLA-4 monoclonal antibodies [eg, Ipilimumab (YERVOY TM ), etc.], PD-1 monoclonal antibodies [Nivolumab (Opdivo TM ), Pembrolizumab (Keytruda TM ), etc.], PD -L1 monoclonal antibodies [Atezolizumab (TECENTRIQ TM ), Durvalumab (IMFINZI TM ), etc.] are known. However, it is known that immune checkpoint inhibitors respond successfully to only a portion of the entire cancer patient population and overcome side effects such as autoimmune diseases.
트립토판은 세포 증식 및 생존을 위해서 필수적인 아미노산이다. 인돌아민 2,3-디옥시게나아제 1(통상, 'IDO-1'으로도 지칭된다)는 필수 아미노산인 L-트립토판을 N-포르밀-키누레닌으로의 분해하는 제1 단계인 속도-결정 단계를 촉매하는 헴-함유 세포 내 효소이다. IDO-1은 L-트립토판의 대사에 작용하여 N-포르밀-키누레닌으로 분해하고, N-포르밀-키누레닌은 다양한 단계에 의해서 대사되어 니코틴아미드 아데닌 디뉴클레오티드(NAD+)를 생성한다. N-포르밀-키누레닌로부터 생성된 트립토판 분해대사산물(catabolite), 예컨대 키누레닌은 T-세포에 세포독성이 있다고 알려져 있다. IDO의 작용은 트립토판을 고갈시키고, 키누레닌을 생성시키며, 이 두 가지는 서로 협력하여 다양한 메커니즘을 통해 T-세포를 비롯한 면역세포들의 활성을 저해한다(Mellor, A. L. & Munn, D. H. Nature Rev. Immunol. 8, 74-80 (2008), Fallarino, F., Gizzi, S., Mosci, P., Gronmann, U. & Puccetti, P. Curr. Drug Metab. 8, 209-216 (2007)). IDO-1는 암세포는 물론 수지상 세포(dendritic cells)와 조절 B 세포(regulatory B cell)에 분포되어 있으며, 이러한 세포에 작용하여 면역계가 암세포를 인식, 공격하는 능력을 억제한다. 따라서, IDO-1의 과발현은 종양 미세환경(tumor microenvironment)에서 내성 증가로 이어질 수 있고 이는 암 조직을 키우는데 작용한다. Tryptophan is an essential amino acid for cell proliferation and survival. Indolamine 2,3-dioxygenase 1 (commonly referred to as 'IDO-1') is the first, rate-determining step in the degradation of L-tryptophan, an essential amino acid, into N-formyl-kynurenine. It is a heme-containing intracellular enzyme that catalyzes IDO-1 acts on the metabolism of L-tryptophan to break it down into N-formyl-kynurenine, and N-formyl-kynurenine is metabolized by various steps to produce nicotinamide adenine dinucleotide (NAD+). Tryptophan catabolites produced from N-formyl-kynurenine, such as kynurenine, are known to be cytotoxic to T-cells. The action of IDO depletes tryptophan and produces kynurenine, and these two cooperate with each other to inhibit the activity of immune cells including T-cells through various mechanisms (Mellor, A. L. & Munn, D. H. Nature Rev. Immunol. 8, 74-80 (2008), Fallarino, F., Gizzi, S., Mosci, P., Gronmann, U. & Puccetti, P. Curr. Drug Metab. 8, 209-216 (2007)). IDO-1 is distributed in dendritic cells and regulatory B cells as well as cancer cells, and acts on these cells to suppress the ability of the immune system to recognize and attack cancer cells. Therefore, overexpression of IDO-1 can lead to increased resistance in the tumor microenvironment, which acts to grow cancer tissue.
암 환자의 경우, IDO-1이 상향조절되어 있으면 예후가 불량해지는 것으로 보고 되어 있다(Uyttenhove, C. et al. Nature Med. 9, 1269-1274 (2003)). 마우스의 IDO-1 유전자를 제거한 시험으로부터, IDO-1이 면역 관용과 염증성 발암(inflammatory carcinogenesis) 과정에서 핵심적인 역할을 하는 것으로 확인된 바 있다(Muller, A. J., Mandik-Nayak, L. & Prendergast, G. C. Immunotherapy 2, 293-297 (2010) Muller, A. J. et al. Proc. Natl Acad. Sci. USA 105, 17073-17078 (2008)). 특히 IDO-1 저해제를 보조 치료제로 사용할 경우 면역화학요법, 방사선요법, 항암 백신의 효과를 개선할 수 있다고 보고된 바 있다(Muller, A. J., DuHadaway, J. B., Donover, P. S., Sutanto-Ward, E. & Prendergast, G. C. Nature Med. 11, 312-319 (2005)). 또한, 항암제 이마티닙(글리벡)이 고형 위장관 기질종양(solid gastrointestinal stromal tumor)에 강한 효과를 보이는 이유가 IDO-1을 저해하기 때문인 것으로 보고된 바 있다(Balachandran, V. P. et al. Nature Med. 17, 1094-1100 (2011)). In the case of cancer patients, it has been reported that if IDO-1 is upregulated, the prognosis becomes poor (Uyttenhove, C. et al. Nature Med. 9, 1269-1274 (2003)). From tests in which the IDO-1 gene was removed from mice, it was confirmed that IDO-1 plays a key role in the process of immune tolerance and inflammatory carcinogenesis (Muller, A. J., Mandik-Nayak, L. & Prendergast, G. C. Immunotherapy 2, 293-297 (2010) Muller, A. J. et al. Proc. Natl Acad. Sci. USA 105, 17073-17078 (2008)). In particular, it has been reported that the use of IDO-1 inhibitors as adjuvant treatments can improve the effects of immunochemotherapy, radiotherapy, and anticancer vaccines (Muller, A. J., DuHadaway, J. B., Donover, P. S., Sutanto-Ward, E. & Prendergast, G. C. Nature Med. 11, 312-319 (2005)). In addition, it has been reported that the reason why the anticancer drug imatinib (Gleevec) shows a strong effect on solid gastrointestinal stromal tumors is because it inhibits IDO-1 (Balachandran, V. P. et al. Nature Med. 17, 1094 -1100 (2011)).
따라서, IDO-1 억제제는 암 전이와 암 증식을 효과적으로 억제할 수 있으며, 바이러스성 감염 및 류마티스 관절염과 같은 자가면역성 질환의 치료 및 예방에 유용하게 사용될 수 있다. 또한, 임신, 악성 종양 또는 바이러스에 의한 T cell 억제 시에 T cell을 활성화하는데 IDO-1 저해제를 사용할 수 있으며, 비록 그 작용이 잘 규명되어 있지는 않지만, 우울증과 같은 신경정신과적 질환이나 증상을 가진 환자의 치료에도 IDO-1 저해제를 사용할 수 있을 것으로 기대된다. 본 발명자들은 특정 사이클로헥실-에틸렌-아미노-헤테로아릴 모이어티를 갖는 유도체 또는 이의 약학적으로 허용가능한 염이 IDO-1에 대하여 우수한 억제 활성을 가질 뿐만 아니라 경구투여시 현저하게 높은 체내 노출을 나타낸다는 발견한 바 있다(대한민국 특허출원 제10-2021-0037824호, 2021년 3월 24일자 출원). 상기 유도체 또는 이의 약학적으로 허용가능한 염은 IDO-1을 매개로 하는 다양한 질환, 예를 들어 암과 같은 증식성 장애, 바이러스 감염 및/또는 자가면역 질환 등의 치료 및 예방에 유용하게 사용될 수 있다. Therefore, IDO-1 inhibitors can effectively inhibit cancer metastasis and cancer growth, and can be usefully used for the treatment and prevention of viral infections and autoimmune diseases such as rheumatoid arthritis. In addition, IDO-1 inhibitors can be used to activate T cells during T cell suppression by pregnancy, malignant tumors or viruses. It is expected that IDO-1 inhibitors can also be used for the treatment of patients. The present inventors have found that a derivative having a specific cyclohexyl-ethylene-amino-heteroaryl moiety or a pharmaceutically acceptable salt thereof not only has an excellent inhibitory activity against IDO-1 but also exhibits remarkably high exposure to the body upon oral administration. (Korean Patent Application No. 10-2021-0037824, filed on March 24, 2021). The derivative or pharmaceutically acceptable salt thereof can be usefully used for the treatment and prevention of various diseases mediated by IDO-1, for example, proliferative disorders such as cancer, viral infections and/or autoimmune diseases. .
본 발명자들은 특정 사이클로헥실-에틸렌-아미노-헤테로아릴 모이어티를 갖는 유도체 또는 이의 약학적으로 허용가능한 염을 면역체크포인트 억제제와 조합하여 투여할 경우, 면역체크포인트 억제제를 단독으로 투여하였을 때보다 상승적인 종양 억제 활성을 나타낸다는 것을 발견하였다.The present inventors have found that when a derivative having a specific cyclohexyl-ethylene-amino-heteroaryl moiety or a pharmaceutically acceptable salt thereof is administered in combination with an immune checkpoint inhibitor, the increase is higher than that when the immune checkpoint inhibitor is administered alone. It was found to exhibit significant tumor suppressive activity.
따라서, 본 발명은 특정 사이클로헥실-에틸렌-아미노-헤테로아릴 모이어티를 갖는 유도체 또는 이의 약학적으로 허용가능한 염과 면역체크포인트 억제제와의 조합을 포함하는 암의 예방 또는 치료용 약학 조성물을 제공하는 것을 목적으로 한다.Accordingly, the present invention provides a pharmaceutical composition for preventing or treating cancer comprising a combination of a derivative having a specific cyclohexyl-ethylene-amino-heteroaryl moiety or a pharmaceutically acceptable salt thereof and an immune checkpoint inhibitor. aims to
또한, 본 발명은 특정 사이클로헥실-에틸렌-아미노-헤테로아릴 모이어티를 갖는 유도체 또는 이의 약학적으로 허용가능한 염을 면역체크포인트 억제제와 조합하여 투여하는 것을 포함하는 암의 치료 방법을 제공하는 것을 목적으로 한다.Another object of the present invention is to provide a method for treating cancer comprising administering a derivative having a specific cyclohexyl-ethylene-amino-heteroaryl moiety or a pharmaceutically acceptable salt thereof in combination with an immune checkpoint inhibitor. to be
본 발명의 일 태양에 따라, 하기 화학식 1의 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 제1 컴파트먼트와 면역체크포인트 억제제를 유효성분으로 포함하는 제2 컴파트먼트와의 조합을 포함하는, 암의 예방 또는 치료용 약학 조성물이 제공된다.According to one aspect of the present invention, the first compartment containing the compound of
<화학식 1><
식 중, during the ceremony,
R1은 C1∼C6 알킬기이고,R 1 is a C 1 -C 6 alkyl group;
A는 벤조[d]옥사졸일 및 퀴나졸린일로 이루어진 군으로부터 선택된 헤테로아릴기이고, 상기 헤테로아릴기는 할로겐 및 C1∼C6 알킬로 이루어진 군으로부터 선택된 1개 또는 2개의 치환기로 치환된다.A is a heteroaryl group selected from the group consisting of benzo[d]oxazolyl and quinazolinyl, and the heteroaryl group is substituted with one or two substituents selected from the group consisting of halogen and C 1 -C 6 alkyl.
본 발명의 다른 태양에 따라, 포유동물에게 치료학적으로 유효한 양의 상기 화학식 1의 화합물 또는 이의 약학적으로 허용가능한 염을 치료학적으로 유효한 양의 면역체크포인트 억제제와 조합하여 투여하는 것을 포함하는, 암의 치료 방법이 제공된다.According to another aspect of the present invention, comprising administering to a mammal a therapeutically effective amount of the compound of Formula 1 or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of an immune checkpoint inhibitor, A method of treating cancer is provided.
본 발명의 또다른 태양에 따라, 포유동물에서 암의 치료를 위한 약제의 제조에 있어서의 사용을 위한 상기 화학식 1의 화합물 또는 이의 약학적으로 허용가능한 염 및 면역체크포인트 억제제와 조합의 용도가 제공된다.According to another aspect of the present invention there is provided the use of a combination of a compound of Formula 1 or a pharmaceutically acceptable salt thereof and an immune checkpoint inhibitor for use in the manufacture of a medicament for the treatment of cancer in a mammal. do.
특정 사이클로헥실-에틸렌-아미노-헤테로아릴 모이어티를 갖는 유도체(즉, 상기 화학식 1의 화합물) 또는 이의 약학적으로 허용가능한 염을 면역체크포인트 억제제와 조합하여 투여할 경우, 면역체크포인트 억제제를 단독으로 투여하였을 때보다 상승적인 종양 억제 활성을 나타낸다는 것이 본 발명에 의해 밝혀졌다. 따라서, 상기 화학식 1의 화합물 또는 이의 약학적으로 허용가능한 염과 면역체크포인트 억제제와의 조합은 암전이와 암재발 억제를 위해 유용하게 적용될 수 있다.When a derivative having a specific cyclohexyl-ethylene-amino-heteroaryl moiety (i.e., a compound of Formula 1) or a pharmaceutically acceptable salt thereof is administered in combination with an immune checkpoint inhibitor, the immune checkpoint inhibitor is administered alone. It was found by the present invention that it exhibits a synergistic tumor suppression activity than when administered as . Therefore, the combination of the compound of Formula 1 or a pharmaceutically acceptable salt thereof and an immune checkpoint inhibitor can be usefully applied to suppress cancer metastasis and cancer recurrence.
도 1a는 실시예 1의 화합물 및 대조물질(BMS-986205)을 랫트에 경구투여한 후 얻어진 혈중농도 프로파일(plasma concentration profiles)이다.
도 1b는 실시예 1의 화합물을 랫드에 경구 투여하여 계산한 가상 혈중 농도 프로파일과 함께, 실시예 2 내지 5의 화합물을 랫트에 경구투여한 후 얻어진 혈중농도 프로파일이다.
도 2는 실시예 1의 화합물과 항-PD-1 항체의 조합 투여에 따른 종양 성장 저해 활성을 평가하여 얻어진 결과를 나타낸다.
도 3은 11일차의 종양 성장 저해를 나타내는 워터폴 플롯(Waterfall plot)이다.
도 4는 MC38 이식된 종양을 갖는 C57BL/6 마우스의 각 군의 생존 곡선을 나타낸다.
도 5a 내지 도 5c는 생존한 개체들 중 완전 치료를 보인 개체들의 종양 부피 추적 곡선을 나타낸다.1a is a plasma concentration profile obtained after oral administration of the compound of Example 1 and a control substance (BMS-986205) to rats.
Figure 1b is a blood concentration profile obtained after orally administering the compound of Examples 2 to 5 to rats together with a virtual blood concentration profile calculated by orally administering the compound of Example 1 to rats.
Figure 2 shows the results obtained by evaluating the tumor growth inhibitory activity according to the combined administration of the compound of Example 1 and the anti-PD-1 antibody.
Figure 3 is a waterfall plot showing inhibition of tumor growth on day 11.
Figure 4 shows survival curves of each group of C57BL/6 mice bearing MC38 transplanted tumors.
5A-5C show tumor volume tracing curves of surviving individuals who showed complete cure.
본 발명은 하기 화학식 1의 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 제1 컴파트먼트와 면역체크포인트 억제제를 유효성분으로 포함하는 제2 컴파트먼트와의 조합을 포함하는, 암의 예방 또는 치료용 약학 조성물을 제공한다.The present invention includes a combination of a first compartment containing the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient and a second compartment containing an immune checkpoint inhibitor as an active ingredient, Provided is a pharmaceutical composition for preventing or treating cancer.
<화학식 1><
식 중, during the ceremony,
R1은 C1∼C6 알킬기이고,R 1 is a C 1 -C 6 alkyl group;
A는 벤조[d]옥사졸일 및 퀴나졸린일로 이루어진 군으로부터 선택된 헤테로아릴기이고, 상기 헤테로아릴기는 할로겐 및 C1∼C6 알킬로 이루어진 군으로부터 선택된 1개 또는 2개의 치환기로 치환된다.A is a heteroaryl group selected from the group consisting of benzo[d]oxazolyl and quinazolinyl, and the heteroaryl group is substituted with one or two substituents selected from the group consisting of halogen and C 1 -C 6 alkyl.
바람직하게는, 제1 컴파트먼트에 포함되는 상기 화학식 1의 화합물은 하기 화합물로 이루어진 군으로부터 선택될 수 있다:Preferably, the compound represented by Formula 1 contained in the first compartment may be selected from the group consisting of the following compounds:
6-클로로-N-((R)-1-((시스)-4-(6-플루오로퀴놀린-4-일)사이클로헥실)프로판-2-일)벤조[d]옥사졸-2-아민;6-chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazol-2-amine ;
6-클로로-N-((R)-1-((시스)-4-(6-플루오로퀴놀린-4-일)싸이클로헥실)부탄-2-일)벤조[d]옥사졸-2-아민;6-chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)butan-2-yl)benzo[d]oxazol-2-amine ;
6-플루오로-N-((R)-1-((시스)-4-(6-플루오로퀴놀린-4-일)사이클로헥실)프로판-2-일)벤조[d]옥사졸-2-아민;6-fluoro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazol-2- amine;
6,7-다이플루오로-N-((R)-1-((시스)-4-(6-플루오로퀴놀린-4-일)사이클로헥실)프로판-2-일)벤조[d]옥사졸-2-아민; 및 6,7-difluoro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole -2-amine; and
2-클로로-N-((R)-1-((시스)-4-(6-플루오로퀴놀린-4-일)사이클로헥실)프로판-2-일)-7-메틸퀴나졸린-4-아민.2-chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-7-methylquinazolin-4-amine .
더욱 바람직하게는, 제1 컴파트먼트에 포함되는 상기 화학식 1의 화합물은 6-클로로-N-((R)-1-((시스)-4-(6-플루오로퀴놀린-4-일)사이클로헥실)프로판-2-일)벤조[d]옥사졸-2-아민일 수 있다.More preferably, the compound of
상기 화학식 1의 화합물은 약학적으로 허용가능한 염의 형태일 수 있다. 상기 염은 통상의 산부가염, 예를 들어 염산, 브롬산, 황산, 설팜산, 인산 또는 질산과 같은 무기산으로부터 유도된 염 및 아세트산, 프로피온산, 숙신산, 글리콜산, 스테아르산, 시트르산, 말레산, 말론산, 메탄술폰산, 타르타르산, 말산, 페닐아세트산, 글루탐산, 벤조산, 살리실산, 2-아세톡시벤조산, 퓨마르산, p-톨루엔술폰산, 옥살산 또는 트리플루오로아세트산과 같은 유기산으로부터 유도된 염을 포함한다. 또한, 상기 염은 통상의 금속 염 형태, 예를 들어 리튬, 나트륨, 칼륨, 마그네슘, 또는 칼슘과 같은 금속으로부터 유도된 염을 포함한다. 상기 산 부가염 또는 금속염은 통상의 방법에 따라 제조될 수 있다.The compound of
상기 화학식 1의 화합물 또는 이의 약학적으로 허용가능한 염은 본 출원인의 선행 출원, 즉 대한민국 특허출원 제10-2021-0037824호(2021년 3월 24일자 출원)에 따라 제조될 수 있다. 예를 들어, 상기 화학식 1의 화합물 또는 이의 약학적으로 허용가능한 염은 화학식 2의 화합물 또는 이의 염을 화학식 3의 화합물과 반응시켜 화학식 1의 화합물을 얻는 단계; 및 선택적으로, 상기 화학식 1의 화합물을 이의 약학적으로 허용가능한 염으로 전환하는 단계를 포함하는 제조방법에 의해 제조될 수 있다.The compound of
<화학식 2><Formula 2>
<화학식 3><Formula 3>
X-AX-A
식 중, R1 및 A는 상기에서 정의한 바와 동일하며, X는 할로겐이다.In the formula, R 1 and A are as defined above, and X is halogen.
화학식 3의 화합물은 상업적으로 구입가능하다. 상기 화학식 2의 화합물 또는 이의 염(예를 들어, 염산염)과 화학식 3의 화합물과의 반응은 염기 및 용매 존재하에서 수행될 수 있다. 상기 염기는 탄산세슘, 탄산칼륨, 탄산나트륨, 트라이에틸아민 등일 수 있으며, 상기 용매는 N,N-다이메틸포름아마이드, 1,4-다이옥산, 테트라하이드로퓨란, 에탄올, 아이소프로필 알콜 등의 유기 용매일 수 있다. 또한 상기 반응은 상온 내지 100℃에서 수행될 수 있다.Compounds of Formula 3 are commercially available. The reaction between the compound of Formula 2 or a salt thereof (eg, hydrochloride) and the compound of Formula 3 may be carried out in the presence of a base and a solvent. The base may be cesium carbonate, potassium carbonate, sodium carbonate, triethylamine, etc., and the solvent may be an organic solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, ethanol, isopropyl alcohol, etc. can In addition, the reaction may be carried out at room temperature to 100 ℃.
상기 화학식 2의 화합물 또는 이의 염은 예를 들어, 하기 반응식 1에 따라 제조될 수 있다.The compound of Formula 2 or a salt thereof may be prepared, for example, according to
<반응식 1><
상기 반응식 1에서, R1은 상기에서 정의한 바와 동일하다.In
상기 화학식 5의 화합물은 상업적으로 구입 가능한 화학식 4의 화합물과 4-클로로-6-플루오로퀴놀린을 스즈키(Suzuki) 반응을 통하여 제조될 수 있다. 상기 반응은 팔라듐 촉매를 사용하여 수행할 수 있으며, 상기 팔라듐 촉매는 팔라듐(II)아세테이트(Pd(OAc)2), 트리스(다이벤질리덴아세톤)다이팔라듐(tris(dibenzylideneacetone)dipalladium, Pd2(dba)3), 테트라키스(트라이페닐포스핀)팔라듐(0)(Pd(PPh3)4) 또는 [1,1'-비스(다이페닐포스피노)페로센]다이클로로팔라듐(II)(Pd(dppf)Cl2) 등을 포함한다. 팔라듐 촉매 이외에 리간드 및 염기를 첨가하여 반응을 수행할 수 있다. 상기 리간드는 (S)-2,2-비스(다이페닐포스피노)-1,1-바이나프틸(BINAP), 1,1'-비스(다이페닐포스피노)페로센(dppf) 또는 (트라이-O-톨릴)포스핀 (P(O-Tol)3) 등을 포함한다. 상기 염기는 세슘 카보네이트(Cs2CO3), 소듐 카보네이트(Na2CO3), 포타슘 카보네이트(K2CO3), 포타슘 플루오라이드(KF), 세슘 플루오라이드(CsF), 소듐 하이드록사이드(NaOH), 포타슘 포스페이트(K3PO4), 소듐 tert-부톡사이드(tert-BuONa) 또는 포타슘 tert-부톡사이드(tert-BuOK) 등의 무기 염기를 포함한다. 상기 반응은 벤젠 또는 톨루엔과 같은 비극성 유기용매 또는 1,4-다이옥산, 테트라하이드로퓨란, 아세토니트릴, 1,2-다이메톡시에탄, 또는 N,N-다이메틸포름아마이드 등의 극성 유기용매 중에서, 50℃ 내지 150℃에서, 바람직하게는 80℃ 내지 110℃에서 수행될 수 있다. 반응 시간을 포함한 기타 반응조건은 스즈키(Suzuki) 반응에 대한 공지의 방법에 따라 수행할 수 있다(Barbara Czako와 Laszlo Kurti, STRATEGIC APPLICATIONS of NAMED REACTIONS in ORGANIC SYNTHESIS, 2005).The compound of Formula 5 may be prepared through a Suzuki reaction between a commercially available compound of
상기 화학식 5의 화합물의 환원은, 에틸 아세테이트 또는 메탄올 등의 유기 용매 중에서, 팔라듐/카본을 사용하여 수행할 수 있다. 상기 환원 반응은 전형적으로 수소를 이용하여 상온에서 수행될 수 있다. Reduction of the compound of Formula 5 may be performed using palladium/carbon in an organic solvent such as ethyl acetate or methanol. The reduction reaction can typically be carried out at room temperature using hydrogen.
상기 화학식 6의 화합물의 환원은, 테트라하이드로퓨란 또는 다이클로로메탄 등의 유기 용매 중에서, 리튬 알루미늄 하이드라이드를 사용하여 수행할 수 있다. 상기 환원 반응은 전형적으로 -78℃ 내지 상온에서 수행될 수 있다.Reduction of the compound of Formula 6 may be performed using lithium aluminum hydride in an organic solvent such as tetrahydrofuran or dichloromethane. The reduction reaction may be typically carried out at -78°C to room temperature.
상기 화학식 7의 화합물의 산화는, 에틸 아세테이트 또는 다이클로로메탄 등의 유기 용매 중에서, 산화제를 사용하여 수행할 수 있다. 상기 산화 반응은 전형적으로 0℃ 내지 상온에서 수행될 수 있다. Oxidation of the compound of Formula 7 may be performed using an oxidizing agent in an organic solvent such as ethyl acetate or dichloromethane. The oxidation reaction may typically be carried out at 0°C to room temperature.
상기 화학식 9의 화합물은 화학식 8의 화합물과 (S)-(-)-2-메틸-2-프로판설핀아마이드의 축합에 의해 제조될 수 있다. 상기 축합은, 티타늄(IV) 아이소프로폭사이드, 티타늄(IV) 에폭사이드 등의 루이스 산 촉매의 존재하에, 에틸 아세테이트, 다이클로로메탄, 테트라하이드로퓨란 등의 유기 용매 중에서 수행할 수 있다. 상기 반응은 -78℃ 내지 상온에서 수행될 수 있다. The compound of Formula 9 may be prepared by condensation of the compound of
상기 화학식 9의 화합물을 알킬 그리그나드(alkyl Grignard) 시약과 반응시켜 화학식 10의 화합물을 제조할 수 있다. 또한, 상기 화학식 10 화합물을 탈보호하여 화학식 2의 화합물 또는 이의 염(예를 들어, 염산염 등)을 제조할 수 있다. 상기 탈보호 반응은 공지의 방법(Theodora W. Greene과 Peter G. M. Wuts, Protective groups in organic synthesis, 3rd Ed., 1999)에 따라 수행될 수 있다. 예를 들어, 상기 탈보호 반응은, 다이클로로메탄, 1,4-다이옥산 또는 에틸 아세테이트 등의 유기용매 중에서, 트라이플루오로아세트산 또는 염산 용액을 사용하여, 상온에서 수행될 수 있다. The compound of
본 발명의 약학 조성물에 있어서, 상기 면역체크포인트 억제제는 예를 들어 PD-1/PD-L1 신호전달(Programmed Death Receptor-1(PD-1)/Programmed Death Ligand-1(PD-L1) signaling pathway, PD-1/PD-L1 signaling pathway) 억제제일 수 있다. 상기 면역체크포인트 억제제는 바람직하게는 항-CTLA-4 항체[예를 들어, 이피리무맙(Ipilimumab) 등], 항-PD-1 항체[니볼루맙(Nivolumab), 펨브롤리주맙(Pembrolizumab) 등], 또는 항-PD-L1 항체[아테졸리주맙(Atezolizumab), 두르발루맙(Durvalumab) 등]일 수 있으며, 더욱 바람직하게는 항-PD-1 항체[니볼루맙(Nivolumab), 펨브롤리주맙(Pembrolizumab) 등]일 수 있으나, 이에 제한되는 것은 아니다. 상기 항체는 모노클로날 항체 또는 이의 항원 결합 단편일 수 있다. 상기 항원 결합 단편은 모노클로날 항체의 항원과 결합할 수 있는 기능을 보유하고 있는 단편을 의미하며, Fab, Fab', F(ab')2, scFv (scFv)2, scFv-Fc, 및 Fv 등을 포함한다.In the pharmaceutical composition of the present invention, the immune checkpoint inhibitor is, for example, the PD-1 / PD-L1 signaling pathway (Programmed Death Receptor-1 (PD-1) / Programmed Death Ligand-1 (PD-L1) signaling pathway , PD-1/PD-L1 signaling pathway) inhibitors. The immune checkpoint inhibitor is preferably an anti-CTLA-4 antibody (eg, Ipilimumab, etc.), an anti-PD-1 antibody (Nivolumab, Pembrolizumab, etc.) , or an anti-PD-L1 antibody [Atezolizumab, Durvalumab, etc.], more preferably an anti-PD-1 antibody [Nivolumab, Pembrolizumab ), etc.], but is not limited thereto. The antibody may be a monoclonal antibody or an antigen-binding fragment thereof. The antigen-binding fragment refers to a fragment that retains the function of binding to an antigen of a monoclonal antibody, and includes Fab, Fab', F(ab')2, scFv (scFv)2, scFv-Fc, and Fv Include etc.
본 발명의 약학 조성물에 있어서, 상기 암은 고형 종양일 수 있으며, 예를 들어 편평세포암종, 골수종, 소세포폐암, 비-소세포폐암, 신경교종, 호지킨 림프종, 비-호지킨 림프종, 급성 골수성 백혈병, 다발성 골수종, 위장관 암, 신장암, 난소암, 간암, 림프아구성 백혈병, 림프구성 백혈병, 결장직장암, 자궁내막암, 전립선암, 갑상선암, 흑색종, 연골육종, 신경모세포종, 췌장암, 다형성 교모세포종, 자궁경부암, 뇌암, 방광암, 유방암, 결장암종, 요로상피암, 두경부암 등일 수 있으나, 이에 제한되는 것은 아니다.In the pharmaceutical composition of the present invention, the cancer may be a solid tumor, for example, squamous cell carcinoma, myeloma, small cell lung cancer, non-small cell lung cancer, glioma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, acute myelogenous leukemia , multiple myeloma, gastrointestinal cancer, kidney cancer, ovarian cancer, liver cancer, lymphoblastic leukemia, lymphocytic leukemia, colorectal cancer, endometrial cancer, prostate cancer, thyroid cancer, melanoma, chondrosarcoma, neuroblastoma, pancreatic cancer, glioblastoma multiforme , cervical cancer, brain cancer, bladder cancer, breast cancer, colon carcinoma, urothelial cancer, head and neck cancer, etc., but is not limited thereto.
본 발명의 약학 조성물에 있어서, 상기 제1 컴파트먼트가 경구투여용 컴파트먼트이고, 상기 제2 컴파트먼트는 주사용 컴파트먼트일 수 있다. 따라서, 상기 제1 컴파트먼트는 제제학 분야에서 통상적으로 사용되는 부형제(예를 들어 락토즈, 옥수수전분 등), 붕해제, 활택제(마그네슘 스테아레이트 등) 등의 약학적으로 허용가능한 담체를 포함할 수 있으며, 통상의 방법에 따라 정제, 캅셀제, 산제, 과립제 및 현탁제, 유제 또는 시럽제와 같은 경구용 제제로 제제화될 수 있다. 상기 경구용 제제 형태의 제1 컴파트먼트는 예를 들어 단회 투여형 또는 수회 투여형 투여 형태(dosage form)일 수 있다. 상기 제2 컴파트먼트는 주사제 등의 비경구 투여용 제제의 형태, 예를 들어 근육내, 복강내, 피하 또는 정맥내 투여에 적합한 형태일 수 있으며, 단회 투여형 또는 수회 투여형 투여 형태(dosage form)일 수 있다. 상기 주사제는 면역체크포인트 억제제의 멸균 용액이 통상 제조되며, 용액의 pH를 적합하게 조절하고 완충시켜야 한다. 정맥내 투여의 경우, 용질의 총 농도는 제제에 등장성이 부여되도록 조절되어야 한다. 상기 제2 컴파트먼트는 pH가 7.4인 염수와 같은 약제학적으로 허용되는 담체를 포함하는 수용액제의 형태일 수 있다.In the pharmaceutical composition of the present invention, the first compartment may be an oral administration compartment, and the second compartment may be an injection compartment. Therefore, the first compartment contains pharmaceutically acceptable carriers such as excipients (for example, lactose, corn starch, etc.), disintegrants, and lubricants (magnesium stearate, etc.) commonly used in the field of pharmaceuticals. and may be formulated into oral preparations such as tablets, capsules, powders, granules and suspensions, emulsions or syrups according to conventional methods. The first compartment of the oral dosage form may be, for example, a single-dose or multi-dose dosage form. The second compartment may be in the form of a preparation for parenteral administration such as an injection, for example, a form suitable for intramuscular, intraperitoneal, subcutaneous or intravenous administration, and may be a single or multiple dose dosage form. form) can be For the injection, a sterile solution of an immune checkpoint inhibitor is usually prepared, and the pH of the solution must be appropriately adjusted and buffered. For intravenous administration, the total concentration of solutes should be adjusted to impart isotonicity to the formulation. The second compartment may be in the form of an aqueous solution containing a pharmaceutically acceptable carrier such as saline having a pH of 7.4.
본 발명의 약학 조성물의 일 구현예에서, 상기 제1 컴파트먼트는 상기 화학식 1의 화합물 또는 이의 약학적으로 허용가능한 염 5 내지 200 mg/kg의 투여량으로, 1일 1 내지 4회 경구투여될 수 있다. 바람직한 구현예에서, 상기 제1 컴파트먼트는 상기 화학식 1의 화합물 또는 이의 약학적으로 허용가능한 염 10 내지 20 mg/kg의 투여량으로, 1일 1 내지 2회 경구투여될 수 있다. 물론, 상기 투여량 및 투여횟수는 환자의 상태, 나이, 암의 심각성 등에 따라 적절히 조절될 수 있다.In one embodiment of the pharmaceutical composition of the present invention, the first compartment is administered orally 1 to 4 times a day at a dose of 5 to 200 mg/kg of the compound of
본 발명의 약학 조성물의 다른 구현예에서, 상기 제2 컴파트먼트는 상기 면역체크포인트 억제제 0.005 내지 10 mg/kg의 투여량으로, 1주 1 내지 5회 주사될 수 있다. 바람직한 구현예에서, 상기 제2 컴파트먼트가 항-PD-1 항체 1 내지 10 mg/kg의 투여량으로, 1주 1 내지 5회 주사될 수 있다. 물론, 상기 투여량 및 투여횟수는 환자의 상태, 나이, 암의 심각성 등에 따라 적절히 조절될 수 있다.In another embodiment of the pharmaceutical composition of the present invention, the second compartment may be injected 1 to 5 times a week at a dose of 0.005 to 10 mg/kg of the immune checkpoint inhibitor. In a preferred embodiment, the second compartment is injected at a dose of 1 to 10 mg/kg of the anti-PD-1 antibody, 1 to 5 times per week. Of course, the dosage and frequency of administration may be appropriately adjusted according to the patient's condition, age, severity of cancer, and the like.
본 발명은 또한 포유동물에게 치료학적으로 유효한 양의 하기 화학식 1의 화합물 또는 이의 약학적으로 허용가능한 염을 치료학적으로 유효한 양의 면역체크포인트 억제제와 조합하여 투여하는 것을 포함하는, 암의 치료 방법을 제공한다.The present invention also relates to a method for treating cancer comprising administering to a mammal a therapeutically effective amount of a compound of
<화학식 1><
식 중, during the ceremony,
R1은 C1∼C6 알킬기이고,R 1 is a C 1 -C 6 alkyl group;
A는 벤조[d]옥사졸일 및 퀴나졸린일로 이루어진 군으로부터 선택된 헤테로아릴기이고, 상기 헤테로아릴기는 할로겐 및 C1∼C6 알킬로 이루어진 군으로부터 선택된 1개 또는 2개의 치환기로 치환된다.A is a heteroaryl group selected from the group consisting of benzo[d]oxazolyl and quinazolinyl, and the heteroaryl group is substituted with one or two substituents selected from the group consisting of halogen and C 1 -C 6 alkyl.
바람직하게는, 상기 화학식 1의 화합물은 하기 화합물로 이루어진 군으로부터 선택될 수 있다:Preferably, the compound of
6-클로로-N-((R)-1-((시스)-4-(6-플루오로퀴놀린-4-일)사이클로헥실)프로판-2-일)벤조[d]옥사졸-2-아민;6-chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazol-2-amine ;
6-클로로-N-((R)-1-((시스)-4-(6-플루오로퀴놀린-4-일)싸이클로헥실)부탄-2-일)벤조[d]옥사졸-2-아민;6-chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)butan-2-yl)benzo[d]oxazol-2-amine ;
6-플루오로-N-((R)-1-((시스)-4-(6-플루오로퀴놀린-4-일)사이클로헥실)프로판-2-일)벤조[d]옥사졸-2-아민;6-fluoro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazol-2- amine;
6,7-다이플루오로-N-((R)-1-((시스)-4-(6-플루오로퀴놀린-4-일)사이클로헥실)프로판-2-일)벤조[d]옥사졸-2-아민; 및 6,7-difluoro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole -2-amine; and
2-클로로-N-((R)-1-((시스)-4-(6-플루오로퀴놀린-4-일)사이클로헥실)프로판-2-일)-7-메틸퀴나졸린-4-아민.2-chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-7-methylquinazolin-4-amine .
더욱 바람직하게는, 상기 화학식 1의 화합물은 6-클로로-N-((R)-1-((시스)-4-(6-플루오로퀴놀린-4-일)사이클로헥실)프로판-2-일)벤조[d]옥사졸-2-아민일 수 있다.More preferably, the compound of
본 발명의 치료 방법에 있어서, 화학식 1의 화합물 또는 이의 약학적으로 허용가능한 염, 면역체크포인트 억제제, 및 암의 종류는 본 발명의 약학 조성물과 관련하여 설명한 바와 동일하다.In the treatment method of the present invention, the compound of
본 발명의 치료 방법의 일 구현예에서, 상기 화학식 1의 화합물 또는 이의 약학적으로 허용가능한 염은 경구투여되고, 상기 면역체크포인트 억제제는 주사될 수 있다. 따라서, 상기 화학식 1의 화합물 또는 이의 약학적으로 허용가능한 염은 경구투여용 형태로 투여될 수 있으며, 상기 경구투여용 형태는 본 발명의 약학 조성물에서 제1 컴파트먼트와 관련하여 설명한 바와 동일하다. 또한, 상기 면역체크포인트 억제제는 주사제의 형태로 투여될 수 있으며, 상기 주사제 등의 비경구 투여용 제제의 형태는 본 발명의 약학 조성물에서 제2 컴파트먼트와 관련하여 설명한 바와 동일하다.In one embodiment of the treatment method of the present invention, the compound of
본 발명의 치료 방법의 일 구현예에서, 상기 화학식 1의 화합물 또는 이의 약학적으로 허용가능한 염은 5 내지 200 mg/kg의 투여량으로, 1일 1 내지 4회 경구투여될 수 있다. 바람직한 구현예에서, 상기 화학식 1의 화합물 또는 이의 약학적으로 허용가능한 염은 10 내지 20 mg/kg의 투여량으로, 1일 1 내지 2회 경구투여될 수 있다. 물론, 상기 투여량 및 투여횟수는 환자의 상태, 나이, 암의 심각성 등에 따라 적절히 조절될 수 있다.In one embodiment of the treatment method of the present invention, the compound of
본 발명의 치료 방법의 다른 구현예에서, 상기 면역체크포인트 억제제는 0.005 내지 10 mg/kg의 투여량으로, 1주 1 내지 5회 주사될 수 있다. 바람직한 구현예에서, 항-PD-1 항체는 1 내지 10 mg/kg의 투여량으로, 1주 1 내지 5회 주사될 수 있다. 물론, 상기 투여량 및 투여횟수는 환자의 상태, 나이, 암의 심각성 등에 따라 적절히 조절될 수 있다.In another embodiment of the treatment method of the present invention, the immune checkpoint inhibitor may be injected at a dose of 0.005 to 10 mg/kg, 1 to 5 times a week. In a preferred embodiment, the anti-PD-1 antibody is injected at a dose of 1 to 10 mg/kg, 1 to 5 times per week. Of course, the dosage and frequency of administration may be appropriately adjusted according to the patient's condition, age, severity of cancer, and the like.
본 발명은 또한 포유동물에서 암의 치료를 위한 약제의 제조에 있어서의 사용을 위한 상기 화학식 1의 화합물 또는 이의 약학적으로 허용가능한 염 및 면역체크포인트 억제제와 조합의 용도를 제공한다. 본 발명의 용도에 있어서, 화학식 1의 화합물 또는 이의 약학적으로 허용가능한 염, 면역체크포인트 억제제, 및 암의 종류는 본 발명의 약학 조성물과 관련하여 설명한 바와 동일하다. 또한, 상기 화학식 1의 화합물 또는 이의 약학적으로 허용가능한 염 및 면역체크포인트 억제제를 각각 포함하는 형태, 투여량, 투여방법 등은 본 발명의 치료 방법과 관련하여 설명한 바와 동일하다. The present invention also provides the use of a compound of
이하, 본 발명을 실시예 및 시험예를 통하여 더욱 상세히 설명한다. 그러나, 이들 실시예 및 시험예는 본 발명을 예시하는 것이며, 본 발명이 이들에 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail through examples and test examples. However, these Examples and Test Examples illustrate the present invention, and the present invention is not limited thereto.
하기 실시예들에서 제조된 화합물들의 분석은 다음과 같이 수행하였다: 핵자기 공명(NMR) 스펙트럼 분석은 브루커(Bruker) 400 MHz 분광계 상에서 수행하였고, 화학이동(chemical shift)은 ppm으로 분석하였으며, 컬럼 크로마토그라피는 실리카겔(Merck, 70-230 mesh) 상에서 수행하였다(W.C. Still, J. Org. Chem., 43, 2923, 1978). 출발물질은 공지의 화합물로 문헌에 따라 합성하거나, 시그마 알드리치사 등으로부터 구입하였다.Analysis of the compounds prepared in the following examples was performed as follows: nuclear magnetic resonance (NMR) spectral analysis was performed on a Bruker 400 MHz spectrometer, chemical shifts were analyzed in ppm, Column chromatography was performed on silica gel (Merck, 70-230 mesh) (W. C. Still, J. Org. Chem., 43, 2923, 1978). Starting materials were known compounds that were synthesized according to the literature or purchased from Sigma-Aldrich, etc.
실시예 1. 6-클로로-N-((R)-1-((시스)-4-(6-플루오로퀴놀린-4-일)사이클로헥실)프로판-2-일)벤조[d]옥사졸-2-아민Example 1. 6-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole -2-amine
단계 1: 에틸 2-(4-(6-플루오로퀴놀린-4-일)사이클로헥스-3-엔-1-일)아세테이트Step 1: Ethyl 2-(4-(6-fluoroquinolin-4-yl)cyclohex-3-en-1-yl)acetate
에틸 2-(4-(4,4,5,5-테트라메틸-1,3,2-다이옥사보롤란-2-일)사이클로헥스-3-엔-1-일)아세테이트(5.83 g), 4-클로로-6-플루오로퀴놀린(3.00 g), 및 소듐 카보네이트(5.35 g)를 1,4-다이옥산(30 ml)과 물(30 ml)의 혼합 용매에 녹이고, [1,1'-비스(다이페닐포스피노)페로센]다이클로로팔라듐(II)(Pd(dppf)Cl2)(675 mg)를 가하여, 95℃에서 밤새 교반하였다. 반응 혼합물을 농축한 후, 에틸 아세테이트를 가하고, 증류수로 세척한 후, 무수 황산마그네슘으로 건조하고, 감압 농축하여 황색의 액상 잔사를 얻었다. 상기 잔사를 실리카겔 컬럼 크로마토그라피(전개용매: n-헥산/에틸 아세테이트 = 1/1, v/v)로 정제하여 백색 고체의 표제 화합물 4.40 g을 제조하였다. (수율: 82.4 %)Ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)acetate (5.83 g), 4 -Chloro-6-fluoroquinoline (3.00 g) and sodium carbonate (5.35 g) were dissolved in a mixed solvent of 1,4-dioxane (30 ml) and water (30 ml), [1,1'-bis( Diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl 2 ) (675 mg) was added and stirred at 95°C overnight. After concentrating the reaction mixture, ethyl acetate was added, washed with distilled water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a yellow liquid residue. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 1/1, v/v) to obtain 4.40 g of the title compound as a white solid. (Yield: 82.4%)
1H-NMR (CDCl3) δ 8.79 (d, 1H), 8.10 (t, 1H), 7.61 (d, 1H), 7.51 (t, 1H). 7.18 (d, 1H), 5.81 (s, 1H), 4.18 (q, 2H), 2.51-2.28 (m, 7H), 2.02 (m, 2H), 1.58 (m, 1H), 1.28 (t, 3H) 1 H-NMR (CDCl 3 ) δ 8.79 (d, 1H), 8.10 (t, 1H), 7.61 (d, 1H), 7.51 (t, 1H). 7.18 (d, 1H), 5.81 (s, 1H), 4.18 (q, 2H), 2.51-2.28 (m, 7H), 2.02 (m, 2H), 1.58 (m, 1H), 1.28 (t, 3H)
단계 2: 에틸 2-(4-(6-플루오로퀴놀린-4-일)사이클로헥실)아세테이트Step 2: Ethyl 2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)acetate
단계 1에서 제조한 에틸 2-(4-(6-플루오로퀴놀린-4-일)사이클로헥스-3-엔-1일)아세테이트(4.40 g) 및 10% Pd/C (440 mg), 초산(0.16 ml)을 메탄올 30 ml에 녹여, 수소 대기하에서 12 시간 교반하였다. 반응 혼합물을 건조 및 여과한 후, 얻어진 잔사를 실리카겔 컬럼 크로마토그라피(전개용매: n-헥산/에틸 아세테이트 = 1/1, v/v)로 정제하여 백색 고체의 표제 화합물 4.17 g을 제조하였다. (수율: 94.2%)Ethyl 2-(4-(6-fluoroquinolin-4-yl)cyclohex-3-en-1yl)acetate (4.40 g) prepared in
1H-NMR (CDCl3) δ 8.80 (s, 1H), 8.11 (t, 1H), 7.65 (d, 1H), 7.46 (t, 1H), 7.30 (d, 1H), 4.16 (q, 2H), 3.21-3.06 (m, 1H), 2.49 (s, 1H), 2.30 (d, 1H), 2.04-1.72 (m, 7H), 1.62 (q, 1H), 1.37-1.24 (m, 4H) 1 H-NMR (CDCl 3 ) δ 8.80 (s, 1H), 8.11 (t, 1H), 7.65 (d, 1H), 7.46 (t, 1H), 7.30 (d, 1H), 4.16 (q, 2H) , 3.21-3.06 (m, 1H), 2.49 (s, 1H), 2.30 (d, 1H), 2.04-1.72 (m, 7H), 1.62 (q, 1H), 1.37-1.24 (m, 4H)
단계 3: 2-(4-(6-플루오로퀴놀린-4-일)사이클로헥실)에탄-1-올Step 3: 2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)ethane-1-ol
단계 2에서 제조한 에틸 2-(4-(6-플루오로퀴놀린-4-일)사이클로헥실)아세테이트(2.27 g)를 테트라하이드로퓨란(24 ml)에 녹여 0℃에서 10분간 교반한 뒤, 리튬 알루미늄 하이드라이드(355 mg)를 천천히 가하였다. 반응 혼합물을 상온에서 6 시간 교반하였다. 물을 가해 반응을 중지한 후, 에틸 아세테이트로 추출하였다. 추출한 유기층을 소금물로 세척하고, 무수 황산마그네슘으로 건조한 다음, 여과하였다. 얻어진 여액을 감압 농축하였다. TLC 상으로 확인되는 두 가지 입체이성질체를 모아 실리카겔 컬럼 크로마토그래피(n-헥산/에틸 아세테이트/=1/2, v/v)로 정제하여 백색 고체상의 표제 화합물 1.53 g을 제조하였다. (수율: 73.2%)Ethyl 2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)acetate (2.27 g) prepared in step 2 was dissolved in tetrahydrofuran (24 ml), stirred at 0 ° C. for 10 minutes, and lithium Aluminum hydride (355 mg) was added slowly. The reaction mixture was stirred at room temperature for 6 hours. After stopping the reaction by adding water, extraction was performed with ethyl acetate. The extracted organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The obtained filtrate was concentrated under reduced pressure. Two stereoisomers confirmed by TLC were collected and purified by silica gel column chromatography (n-hexane/ethyl acetate/=1/2, v/v) to obtain 1.53 g of the title compound as a white solid. (Yield: 73.2%)
1H-NMR (DMSO-d6) δ 8.77 (d, 1H), 8.06 (t, 1H), 7.89 (d, 1H), 7.62 (t, 1H), 7.35 (d, 1H), 4.63(t, 1/2 H), 4.39 (t, 1/2 H), 3.47 (q, 2H), 3.20 (t, 1/2 H), 3.12 (t, 1/2 H), 1.87-1.72 (m, 4H), 1.50-1.36 (m, 4H), 1.21-1.14 (q, 2H) 1 H-NMR (DMSO-d 6 ) δ 8.77 (d, 1H), 8.06 (t, 1H), 7.89 (d, 1H), 7.62 (t, 1H), 7.35 (d, 1H), 4.63 (t, 1/2 H), 4.39 (t, 1/2 H), 3.47 (q, 2H), 3.20 (t, 1/2 H), 3.12 (t, 1/2 H), 1.87-1.72 (m, 4H) ), 1.50-1.36 (m, 4H), 1.21-1.14 (q, 2H)
단계 4: 2-((시스)-4-(6-플루오로퀴놀린-4-일)사이클로헥실)아세트알데하이드Step 4: 2-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)acetaldehyde
단계 3에서 제조한 2-(4-(6-플루오로퀴놀린-4-일)사이클로헥실)에탄-1-올(15.14 g)을 다이클로로메탄(185 ml)에 녹여, 0℃에서 30 분간 교반한 뒤, 데스-마틴 산화제(35.2 g)를 천천히 가하였다. 반응 혼합물을 상온에서 5 시간 교반하였다. 물을 가해 반응을 중지한 후, 에틸 아세테이트로 추출하였다. 추출한 유기층을 소금물로 세척하고, 무수 황산마그네슘으로 건조한 다음, 여과하였다. 얻어진 여액을 감압 농축하였다. 얻어진 잔사를 TLC 상으로 확인되는 두 가지 입체이성질체중 아래의 물질을 실리카겔 컬럼 크로마토그래피(n-헥산/에틸 아세테이트/=3/1, v/v)로 정제하여 백색 고체상의 표제 화합물 8.72 g을 제조하였다. (수율: 57.9%)2- (4- (6-fluoroquinolin-4-yl) cyclohexyl) ethane-1-ol (15.14 g) prepared in step 3 was dissolved in dichloromethane (185 ml) and stirred at 0 ° C for 30 minutes After that, Dess-Martin oxidizer (35.2 g) was added slowly. The reaction mixture was stirred at room temperature for 5 hours. After stopping the reaction by adding water, extraction was performed with ethyl acetate. The extracted organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The obtained filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane/ethyl acetate/=3/1, v/v) to obtain 8.72 g of the title compound as a white solid among two stereoisomers confirmed by TLC. did (Yield: 57.9%)
1H-NMR (CDCl3) δ 9.82 (s, 1H), 8.81 (d, 1H), 8.12 (t, 1H), 7.64 (d, 1H), 7.48 (t, 1H), 7.31 (d, 1H), 3.22 (t, 1H), 2.61 (s, 3H), 1.93-1.67 (m, 8H) 1 H-NMR (CDCl 3 ) δ 9.82 (s, 1H), 8.81 (d, 1H), 8.12 (t, 1H), 7.64 (d, 1H), 7.48 (t, 1H), 7.31 (d, 1H) , 3.22 (t, 1H), 2.61 (s, 3H), 1.93-1.67 (m, 8H)
단계 5: (S)-N-(2-((시스)-4-(6-플루오로퀴놀린-4-일)사이클로헥실)에틸리덴)-2-메틸프로판-2-설핀아마이드Step 5: (S)-N-(2-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethylidene)-2-methylpropane-2-sulfinamide
단계 4에서 제조한 2-((시스)-4-(6-플루오로퀴놀린-4-일)사이클로헥실)아세트알데하이드(4.50 g) 및 (S)-(-)-2-메틸-2-프로판설핀아마이드(4.02 g)를 다이클로로메탄(55 ml)에 녹여, 0℃에서 10 분간 교반한 뒤, 티타늄(IV) 아이소프로폭사이드(9.82 ml)를 천천히 가하였다. 반응 혼합물을 상온에서 8 시간 교반한 뒤, 물을 가해 반응을 중지한 후, 에틸 아세테이트로 추출하였다. 추출한 유기층을 소금물로 세척하고, 무수 황산마그네슘으로 건조한 다음, 여과하였다. 얻어진 여액을 감압 농축하였다. 얻어진 잔사를 실리카겔 컬럼 크로마토그래피(n-헥산/에틸 아세테이트/=1/1, v/v)로 정제하여 백색 고체상의 표제 화합물 5.22 g을 제조하였다. (수율: 84.0%)2-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)acetaldehyde prepared in step 4 (4.50 g) and (S)-(-)-2-methyl-2-propane Sulfinamide (4.02 g) was dissolved in dichloromethane (55 ml), stirred at 0° C. for 10 minutes, and then titanium (IV) isopropoxide (9.82 ml) was slowly added. After stirring the reaction mixture at room temperature for 8 hours, water was added to stop the reaction, and then extracted with ethyl acetate. The extracted organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The obtained filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane/ethyl acetate/=1/1, v/v) to obtain 5.22 g of the title compound as a white solid. (Yield: 84.0%)
1H-NMR (CDCl3) δ 8.82 (1H, d), 8.14-8.10 (m, 2H), 7.64 (d, 1H), 7.46 (t, 1H), 7.33 (d, 1H), 3.22 (t, 1H), 2.72 (t, 2H), 2.04 (s, 1H), 1.95-1.68 (m, 8H), 1.21 (s, 9H) 1 H-NMR (CDCl 3 ) δ 8.82 (1H, d), 8.14-8.10 (m, 2H), 7.64 (d, 1H), 7.46 (t, 1H), 7.33 (d, 1H), 3.22 (t, 1H), 2.72 (t, 2H), 2.04 (s, 1H), 1.95-1.68 (m, 8H), 1.21 (s, 9H)
단계 6: (R)-1-((시스)-4-(6-플루오로퀴놀린-4-일)사이클로헥실)프로판-2-아민 염산염Step 6: (R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-amine hydrochloride
단계 5에서 제조한 (S)-N-(2-((시스)-4-(6-플루오로퀴놀린-4-일)사이클로헥실)에틸리덴)-2-메틸프로판-2-설핀아마이드(2.54 g)를 다이클로로메탄(23 ml)에 녹여, 0℃에서 10 분간 교반한 뒤, 3.0 M 메틸마그네슘 브로마이드(다이에틸 이서 용액)(4.6 ml)를 천천히 가하였다. 반응 혼합물을 상온에서 2 시간 교반한 뒤, 포화 암모늄 클로라이드 수용액을 첨가하여 반응을 중지한 후, 에틸 아세테이트로 추출하였다. 추출한 유기층을 소금물로 세척하고, 무수 황산마그네슘으로 건조한 다음, 여과하였다. 얻어진 여액을 감압 농축하였다. 얻어진 물질을 에틸 아세테이트(25 ml)에 녹이고, 4N 염산 1,4-다이옥산 용액(2 ml)을 적가하고, 상온에서 8 시간 교반하였다. 수득된 고체를 감압 여과하고, 에틸 아세테이트로 세척하여 백색 고체상의 표제 화합물 1.67 g을 제조하였다. (수율 : 86.0%)(S)-N-(2-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethylidene)-2-methylpropane-2-sulfinamide (2.54 g) was dissolved in dichloromethane (23 ml), stirred at 0° C. for 10 minutes, and then 3.0 M methylmagnesium bromide (diethyl ether solution) (4.6 ml) was slowly added. After stirring the reaction mixture at room temperature for 2 hours, the reaction was stopped by adding saturated ammonium chloride aqueous solution, and then extracted with ethyl acetate. The extracted organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The obtained filtrate was concentrated under reduced pressure. The obtained material was dissolved in ethyl acetate (25 ml), 4N hydrochloric acid and 1,4-dioxane solution (2 ml) was added dropwise, and the mixture was stirred at room temperature for 8 hours. The obtained solid was filtered under reduced pressure and washed with ethyl acetate to obtain 1.67 g of the title compound as a white solid. (Yield: 86.0%)
1H-NMR (DMSO-d6) δ 9.23 (d, 1H), 8.56 (t, 1H), 8.42 (d, 1H), 8.27 (s, 2H), 8.08 (t, 2H), 3.63 (s, 1H), 3.19 (s, 1H), 2.11 (m, 11H), 1.26 (d, 3H) 1 H-NMR (DMSO-d 6 ) δ 9.23 (d, 1H), 8.56 (t, 1H), 8.42 (d, 1H), 8.27 (s, 2H), 8.08 (t, 2H), 3.63 (s, 1H), 3.19 (s, 1H), 2.11 (m, 11H), 1.26 (d, 3H)
단계 7: 6-클로로-N-((R)-1-((시스)-4-(6-플루오로퀴놀린-4-일)사이클로헥실)프로판-2-일)벤조[d]옥사졸-2-아민Step 7: 6-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazol- 2-amine
단계 6에서 제조한 (R)-1-((시스)-4-(6-플루오로퀴놀린-4-일)사이클로헥실)프로판-2-아민 염산염(22 mg) 및 2,6-다이클로로벤조옥사졸(15 mg)을 1,4-다이옥산(1.0 ml)에 용해시키고, N,N-다이아이소프로필에틸아민(40 uL)을 서서히 가하였다. 반응 혼합물을 80℃ 에서 12 시간 교반하였다. 반응 혼합물을 상온으로 냉각하고, 물을 가해 반응을 중지한 후, 에틸 아세테이트로 추출하였다. 추출한 유기층을 소금물로 세척하고, 무수 황산마그네슘으로 건조한 다음, 여과하였다. 얻어진 여액을 감압 농축하였다. 얻어진 잔사를 실리카겔 컬럼 크로마토그래피(n-헥산/에틸 아세테이트/=1/2, v/v)로 정제하여 표제 화합물 14.7 mg을 제조하였다. (수율: 43.7 %)(R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-amine hydrochloride prepared in step 6 (22 mg) and 2,6-dichlorobenzo Oxazole (15 mg) was dissolved in 1,4-dioxane (1.0 ml), and N,N-diisopropylethylamine (40 uL) was slowly added. The reaction mixture was stirred at 80°C for 12 hours. The reaction mixture was cooled to room temperature, water was added to stop the reaction, and then extracted with ethyl acetate. The extracted organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The obtained filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate/=1/2, v/v) to obtain 14.7 mg of the title compound. (Yield: 43.7%)
1H-NMR (CDCl3) δ 8.79 (d, 1H), 8.13-8.10 (m, 1H), 7.67-7.64 (d, 1H), 7.49-7.44 (m, 1H), 7.31 (d, 1H), 7.26-7.24 (m, 1H), 7.15 (d, 1H), 4.92 (d, 1H), 4.06-4.02 (m, 1H), 3.21-3.19 (m, 1H), 2.04-2.00 (m, 1H), 1.88-1.64 (m, 11H), 1.36 (d, 3H) 1 H-NMR (CDCl 3 ) δ 8.79 (d, 1H), 8.13-8.10 (m, 1H), 7.67-7.64 (d, 1H), 7.49-7.44 (m, 1H), 7.31 (d, 1H), 7.26-7.24 (m, 1H), 7.15 (d, 1H), 4.92 (d, 1H), 4.06-4.02 (m, 1H), 3.21-3.19 (m, 1H), 2.04-2.00 (m, 1H), 1.88-1.64 (m, 11H), 1.36 (d, 3H)
실시예 2. 6-클로로-N-((R)-1-((시스)-4-(6-플루오로퀴놀린-4-일)싸이클로헥실)부탄-2-일)벤조[d]옥사졸-2-아민Example 2. 6-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)butan-2-yl)benzo[d]oxazole -2-amine
단계 1: (R)-1-((시스)-4-(6-플루오로퀴놀린-4-일)사이클로헥실)부탄-2-아민 염산염Step 1: (R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)butan-2-amine hydrochloride
실시예 1의 단계 5에서 제조한 (S)-N-(2-((시스)-4-(6-플루오로퀴놀린-4-일)사이클로헥실)에틸리덴)-2-메틸프로판-2-설핀아마이드(3.0 g)를 다이클로로메탄(30 ml)에 녹여, -20℃에서 10 분간 교반한 뒤, 1.0 M 에틸마그네슘 브로마이드(THF 용액)(5.34 mL)를 천천히 가하였다. 반응 혼합물을 -20℃에서 6 시간 교반한 뒤, 실온으로 올렸다. 포화 암모늄 클로라이드 수용액을 첨가하여 반응을 중지한 후, 에틸 아세테이트로 추출하였다. 추출한 유기층을 소금물로 세척하고, 무수 황산마그네슘으로 건조한 다음. 여과하였다. 얻어진 여액을 감압 농축하였다. 얻어진 물질을 에틸 아세테이트(30 ml)에 녹이고, 4N 염산 1,4-다이옥산 용액(8 mL)을 적가하고, 상온에서 8 시간 교반하였다. 수득된 고체를 감압 여과하고, 에틸 아세테이트로 세척하여 백색 고체상의 표제 화합물 2.33 g을 제조하였다. (수율 : 86.0%) (S)-N-(2-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)ethylidene)-2-methylpropane-2- prepared in step 5 of Example 1 Sulfinamide (3.0 g) was dissolved in dichloromethane (30 ml), stirred at -20 °C for 10 minutes, and then 1.0 M ethyl magnesium bromide (THF solution) (5.34 mL) was slowly added. The reaction mixture was stirred at -20 °C for 6 hours and then warmed to room temperature. After quenching the reaction by adding a saturated aqueous ammonium chloride solution, extraction was performed with ethyl acetate. The extracted organic layer was washed with brine and dried over anhydrous magnesium sulfate. filtered. The obtained filtrate was concentrated under reduced pressure. The obtained material was dissolved in ethyl acetate (30 ml), 4N hydrochloric acid and 1,4-dioxane solution (8 ml) was added dropwise, and the mixture was stirred at room temperature for 8 hours. The obtained solid was filtered under reduced pressure and washed with ethyl acetate to obtain 2.33 g of the title compound as a white solid. (Yield: 86.0%)
1H-NMR (DMSO-d6) δ 9.21 (d, 1H), 8.57 (q, 1H), 8.40 (d, 1H), 8.26 (s, 2H), 8.08 (q, 2H), 3.61 (s, 1H), 3.01 (s, 1H), 2.00-1.62 (m, 13H), 0.95 (t, 3H) 1 H-NMR (DMSO-d 6 ) δ 9.21 (d, 1H), 8.57 (q, 1H), 8.40 (d, 1H), 8.26 (s, 2H), 8.08 (q, 2H), 3.61 (s, 1H), 3.01 (s, 1H), 2.00-1.62 (m, 13H), 0.95 (t, 3H)
단계 2: 6-클로로-N-((R)-1-((시스)-4-(6-플루오로퀴놀린-4-일)싸이클로헥실)부탄-2-일)벤조[d]옥사졸-2-아민Step 2: 6-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)butan-2-yl)benzo[d]oxazol- 2-amine
단계 1에서 제조한 (R)-1-((시스)-4-(6-플루오로퀴놀린-4-일)사이클로헥실)부탄-2-아민 염산염(70 mg), 2,6-다이클로로벤조옥사졸(32 mg), 및 탄산칼륨(57 mg)을 N,N-다이메틸포름아마이드(1.0 ml)에 용해시키고, 트라이에틸아민(30 uL)을 서서히 가하였다. 반응 혼합물을 80℃ 에서 12 시간 교반하였다. 반응 혼합물을 상온으로 냉각하고, 물을 가해 반응을 중지한 후, 에틸 아세테이트로 추출하였다. 추출한 유기층을 소금물로 세척하고, 무수 황산마그네슘으로 건조한 다음, 여과하였다. 얻어진 여액을 감압 농축하였다. 얻어진 잔사를 실리카겔 컬럼 크로마토그래피(n-헥산/에틸 아세테이트/=1/2, v/v)로 정제하여 표제 화합물 42 mg을 제조하였다. (수율: 44.7 %)(R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)butan-2-amine hydrochloride prepared in step 1 (70 mg), 2,6-dichlorobenzo Oxazole (32 mg), and potassium carbonate (57 mg) were dissolved in N,N-dimethylformamide (1.0 ml), and triethylamine (30 uL) was slowly added. The reaction mixture was stirred at 80°C for 12 hours. The reaction mixture was cooled to room temperature, water was added to stop the reaction, and then extracted with ethyl acetate. The extracted organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The obtained filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane/ethyl acetate/=1/2, v/v) to obtain 42 mg of the title compound. (Yield: 44.7%)
1H-NMR (CDCl3) δ 8.79 (d, 1H), 8.13-8.09 (m, 1H), 7.64 (d, 1H), 7.45 (t, 1H), 7.26-7.21 (m, 3H), 7.14 (d, 1H), 5.60 (s, 1H), 3.88 (s, 1H), 3.19 (s, 1H), 2.04 (s, 1H), 1.82-1.61 (m, 12H), 1.01 (t, 3H) 1 H-NMR (CDCl 3 ) δ 8.79 (d, 1H), 8.13-8.09 (m, 1H), 7.64 (d, 1H), 7.45 (t, 1H), 7.26-7.21 (m, 3H), 7.14 ( d, 1H), 5.60 (s, 1H), 3.88 (s, 1H), 3.19 (s, 1H), 2.04 (s, 1H), 1.82-1.61 (m, 12H), 1.01 (t, 3H)
실시예 3. 6-플루오로-N-((R)-1-((시스)-4-(6-플루오로퀴놀린-4-일)사이클로헥실)프로판-2-일)벤조[d]옥사졸-2-아민Example 3. 6-Fluoro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxa sol-2-amine
실시예 1의 단계 6에서 제조한 (R)-1-((시스)-4-(6-플루오로퀴놀린-4-일)사이클로헥실)프로판-2-아민 염산염(30 mg) 및 2-클로로-6-플루오로-1,3-벤조옥사졸(16 mg)을 1,4-다이옥산(1.0 ml)에 용해시키고, N,N-다이아이소프로필에틸아민(50 uL)을 서서히 가하였다. 반응 혼합물을 100℃ 에서 12 시간 교반하였다. 반응 혼합물을 상온으로 냉각하고, 물을 가해 반응을 중지한 후, 에틸 아세테이트로 추출하였다. 추출한 유기층을 소금물로 세척하고, 무수 황산마그네슘으로 건조한 다음, 여과하였다. 얻어진 여액을 감압 농축하였다. 얻어진 잔사를 실리카겔 컬럼 크로마토그래피(n-헥산/에틸 아세테이트/=1/2, v/v)로 정제하여 표제 화합물 3.9 mg을 제조하였다. (수율: 9.5%)(R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-amine hydrochloride prepared in step 6 of Example 1 (30 mg) and 2-chloro -6-Fluoro-1,3-benzooxazole (16 mg) was dissolved in 1,4-dioxane (1.0 ml), and N,N-diisopropylethylamine (50 uL) was slowly added. The reaction mixture was stirred at 100°C for 12 hours. The reaction mixture was cooled to room temperature, water was added to stop the reaction, and then extracted with ethyl acetate. The extracted organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The obtained filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane/ethyl acetate/=1/2, v/v) to obtain 3.9 mg of the title compound. (Yield: 9.5%)
1H-NMR (CDCl3) δ 8.80 (d, 1H), 8.13-8.10 (m, 1H), 7.64 (d, 1H), 7.49-7.47 (m, 1H), 7.31 (d, 1H), 7.26-7.24 (m, 1H), 7.01 (d, 1H), 6.93-6.88 (m, 1H), 4.74 (m, 1H), 4.05-4.01 (m, 1H), 3.21-3.19 (m, 1H), 2.04-2.00 (m, 1H), 1.88-1.64 (m, 11H), 1.36 (d, 3H) 1 H-NMR (CDCl 3 ) δ 8.80 (d, 1H), 8.13-8.10 (m, 1H), 7.64 (d, 1H), 7.49-7.47 (m, 1H), 7.31 (d, 1H), 7.26- 7.24 (m, 1H), 7.01 (d, 1H), 6.93-6.88 (m, 1H), 4.74 (m, 1H), 4.05-4.01 (m, 1H), 3.21-3.19 (m, 1H), 2.04- 2.00 (m, 1H), 1.88-1.64 (m, 11H), 1.36 (d, 3H)
실시예 4. 6,7-다이플루오로-N-((R)-1-((시스)-4-(6-플루오로퀴놀린-4-일)사이클로헥실)프로판-2-일)벤조[d]옥사졸-2-아민Example 4. 6,7-difluoro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[ d] oxazol-2-amine
실시예 1의 단계 6에서 제조한 (R)-1-((시스)-4-(6-플루오로퀴놀린-4-일)사이클로헥실)프로판-2-아민 염산염(50 mg) 및 2-클로로-6,7-다이플루오로-1,3-벤조옥사졸(33 mg)을 테트라하이드로퓨란(1.0 ml)에 용해시켰다. 얻어진 용액을 씰 튜브에 넣고, 트라이에틸아민(110 μL)를 적가한 다음, 봉인하였다. 반응 혼합물을 120℃에서 12 시간 교반하고, 상온으로 냉각하고, 물을 가해 반응을 중지시킨 후, 에틸 아세테이트로 추출하였다. 추출한 유기층을 소금물로 세척하고, 무수 황산마그네슘으로 건조한 다음, 여과하였다. 얻어진 여액을 감압 농축하였다. 얻어진 잔사를 실리카겔 컬럼 크로마토그래피(n-헥산/에틸 아세테이트/=1/2)로 정제하여 표제 화합물 51.5 mg을 제조하였다. (수율: 75.6 %)(R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-amine hydrochloride prepared in step 6 of Example 1 (50 mg) and 2-chloro -6,7-difluoro-1,3-benzooxazole (33 mg) was dissolved in tetrahydrofuran (1.0 ml). The obtained solution was placed in a sealed tube, triethylamine (110 μL) was added dropwise, and then sealed. The reaction mixture was stirred at 120°C for 12 hours, cooled to room temperature, and water was added to stop the reaction, followed by extraction with ethyl acetate. The extracted organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The obtained filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane/ethyl acetate/=1/2) to obtain 51.5 mg of the title compound. (Yield: 75.6%)
1H-NMR (CDCl3) δ 8.79(d, 1H), 8.12(dd, 1H), 7.64(dd, 1H), 7.48(td, 1H), 7.32(d, 1H), 7.02-6.94(m, 2H), 5.38(d, 1H), 4.04(m, 1H), 3.21(m, 1H), 2.08(br, 1H), 1.81-1.71(m, 10H), 1.38(d, 3H) 1 H-NMR (CDCl 3 ) δ 8.79 (d, 1H), 8.12 (dd, 1H), 7.64 (dd, 1H), 7.48 (td, 1H), 7.32 (d, 1H), 7.02-6.94 (m, 2H), 5.38(d, 1H), 4.04(m, 1H), 3.21(m, 1H), 2.08(br, 1H), 1.81-1.71(m, 10H), 1.38(d, 3H)
실시예 5. 2-클로로-N-((R)-1-((시스)-4-(6-플루오로퀴놀린-4-일)사이클로헥실)프로판-2-일)-7-메틸퀴나졸린-4-아민Example 5. 2-Chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-7-methylquinazoline -4-amine
실시예 1의 단계 6에서 제조한 (R)-1-((시스)-4-(6-플루오로퀴놀린-4-일)사이클로헥실)프로판-2-아민 염산염(50 mg) 및 2,4-다이클로로-7-메틸퀴나졸린(37 mg)을 테트라하이드로퓨란(1.0 ml)에 용해시켰다. 얻어진 용액을 씰 튜브에 넣고, 트라이에틸아민(110 μL)를 적가하고, 봉인하였다. 반응 혼합물을 80℃에서 12 시간 교반하고, 상온으로 냉각하고, 물을 가해 반응을 중지시킨 후, 에틸 아세테이트로 추출하였다. 추출한 유기층을 소금물로 세척하고, 무수 황산마그네슘으로 건조한 다음, 여과하였다. 얻어진 여액을 감압 농축하였다. 얻어진 잔사를 실리카겔 컬럼 크로마토그래피(n-헥산/에틸 아세테이트/=1/2)로 정제하여 미황색 액체상의 표제 화합물 49.5 mg을 제조하였다. (수율: 69.3 %)(R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-amine hydrochloride prepared in step 6 of Example 1 (50 mg) and 2,4 -Dichloro-7-methylquinazoline (37 mg) was dissolved in tetrahydrofuran (1.0 ml). The obtained solution was placed in a sealed tube, triethylamine (110 μL) was added dropwise, and sealed. The reaction mixture was stirred at 80°C for 12 hours, cooled to room temperature, and water was added to stop the reaction, followed by extraction with ethyl acetate. The extracted organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The obtained filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane/ethyl acetate/=1/2) to obtain 49.5 mg of the title compound in the form of a pale yellow liquid. (Yield: 69.3%)
1H-NMR (CDCl3) δ 8.81(d, 1H), 8.12(t, 1H), 7.67(dd, 1H), 7.59-7.56(m, 2H), 7.47(td, 1H), 7.36(d, 1H), 7.28(m, 1H), 5.67(d, 1H), 4.58(m, 1H), 3.21(m, 1H), 2.51(s, 3H), 1.99-1.62(m, 11H), 1.39(d, 3H) 1 H-NMR (CDCl 3 ) δ 8.81 (d, 1H), 8.12 (t, 1H), 7.67 (dd, 1H), 7.59-7.56 (m, 2H), 7.47 (td, 1H), 7.36 (d, 1H), 7.28(m, 1H), 5.67(d, 1H), 4.58(m, 1H), 3.21(m, 1H), 2.51(s, 3H), 1.99-1.62(m, 11H), 1.39(d) , 3H)
시험예 1. IDO1 효소 활성 분석(IDO1 enzyme assay)Test Example 1. IDO1 enzyme activity assay (IDO1 enzyme assay)
IDO1 형광 저해제 검색 시험 키트(IDO1 fluorogenic inhibitor screening assay kit catalog #72037 BPS Bioscience)를 사용하여, 실시예에서 제조한 화합물의 IDO 효소 활성 분석을 수행하였다. 흑색 384 웰 플레이트(black 384 well plate)에 5 ㎕의 시험물질 용액(DMSO 10 ㎕에 실시예의 화합물을 각각 녹인 후, 인산완충식염수(PBS) 90 ㎕와 혼합하여 제조)을 넣고, 5 ㎕의 IDO1 His-tag 효소(40 ng/㎕ in IDO1 assay buffer)를 넣은 후, 37℃에서 2시간 전-인큐베이션하였다. 웰 당 90 ㎕의 IDO1 형광 반응 용액(IDO1 fluorogenic reaction solution)을 넣고, 상온에서 1시간 반응시켰다. 웰 당 20 ㎕의 형광용액(fluorescence solution)을 넣고 37℃에서 4시간 동안 반응시킨 후, 10분간 상온에서 플레이트를 식혀주었다. 형광측정기에서 자극(excitation) 400 nm, 방출(emission) 510 nm에서 형광을 측정하였다. 결과 분석은 IDO 단백질을 포함하고 시험 물질을 처리하지 않은 웰의 형광도(Ft)을 100 %로 하고, IDO 단백질을 포함하지 않고 시험 물질을 처리하지 않은 웰의 형광도(Fb)를 0%로 하여, % 형광도를 계산하였다. Using the IDO1 fluorogenic inhibitor screening assay kit catalog #72037 BPS Bioscience, IDO enzyme activity analysis of the compounds prepared in Examples was performed. In a black 384 well plate, 5 μl of the test substance solution (prepared by dissolving the compounds of the examples in 10 μl of DMSO and then mixing with 90 μl of phosphate buffered saline (PBS)) was added, and 5 μl of IDO1 After adding His-tag enzyme (40 ng/μl in IDO1 assay buffer), pre-incubation was performed at 37°C for 2 hours. 90 μl of IDO1 fluorogenic reaction solution per well was added and reacted at room temperature for 1 hour. After adding 20 μl of fluorescence solution per well and reacting at 37° C. for 4 hours, the plate was cooled at room temperature for 10 minutes. Fluorescence was measured in a fluorescence meter at 400 nm for excitation and 510 nm for emission. For the analysis of the results, the fluorescence (Ft) of wells containing IDO protein and not treated with the test substance was set to 100%, and the fluorescence (Fb) of wells without IDO protein and not treated with the test substance was set to 0%. , and the % fluorescence was calculated.
% Fluorescence = (F-Fb)/(Ft-Fb)% Fluorescence = (F-Fb)/(Ft-Fb)
(F = 시험 물질을 처리한 웰의 형광도)(F = fluorescence of wells treated with test substance)
상기와 같이 얻어진 시험물질의 50% 억제농도(IC50)를 계산하여 얻어진 결과는 하기 표 1과 같다.The results obtained by calculating the 50% inhibitory concentration (IC 50 ) of the test substance obtained as above are shown in Table 1 below.
시험예 2. IDO1 Hela 세포 활성 분석(IDO1 HeLa cell assay)Test Example 2. IDO1 HeLa cell activity assay (IDO1 HeLa cell assay)
세포배양용 96 웰 플레이트(tissue culture-treated 96 well plate)에 배양배지(10% FBS, 페니실린 100 U/ml, 스트렙토마이신 100 ㎍/ml를 함유하는 EMEM) 100 ㎕에 Hela 세포를 20000 cells/well 접종(seeding)하였다. 5% 이산화탄소 배양기(incubator)에서 24시간 배양 후 재조합 인간인터페론 감마(recombinant human Interferon gamma)를 50 ng/ml의 농도로 처리하고, 5% 이산화탄소 배양기에서 48 시간 동안 배양하여 IDO 발현을 유도(induction)시켰다. 20000 cells/well of Hela cells were added to 100 μl of culture medium (EMEM containing 10% FBS, penicillin 100 U/ml, and
IDO1 세포 활성 측정 기질(IDO1 cellular activity quickDetect supplements catalog:#62000-2, BPS Bioscience)을 이용하여 활성을 측정하였다. 구체적으로, 배양배지에 IDO1 분석 배지 기질 1(IDO1 assay medium supplement 1)과 IDO1 분석 배지 기질 2(IDO1 assay medium supplement 2)를 각각 1:100 비율로 희석하여 분석 배지(assay medium)를 준비하였다. 분석 배지에 시험 물질(각각의 실시예의 화합물)을 1 uM부터 1/3씩 희석하여 10개 농도로 만들고, 배양배지를 multi-pipet을 이용하여 제거한 후, 각 웰에 시험물질을 포함한 분석 배지 200 ㎕를 넣고 5% 이산화탄소 배양기에서 24시간 배양하였다. 다음날 각 웰에서 140 ㎕의 배양배지를 새로운 96 웰 플레이트에 옮기고, 6.1N 트라이클로로아세트산을 각 웰에 10 ㎕씩 분주한 후, 50℃ 배양기에 30분간 배양하였다. 플레이트를 2500 rpm에서 10분간 원심분리하여 침전물을 모두 가라앉혔다. 아세트산에 측정시약(detection reagent)(component D 키트, catalog:#62000-2, BPS Bioscience)를 50배 희석하여 측정시약 용액(detection reagent solution)을 제조하였다. 원심분리한 플레이트에서 웰당 100 ㎕의 상등액을 새로운 투명한 96 웰 플레이트에 옮기고, 웰당 100 ㎕의 측정시약 용액을 넣고, 상온에서 10분간 반응시킨 후, 480 nm 파장에서 흡광도를 측정하였다. 결과 분석은 저해제를 처리하지 않고 IDO 단백질 발현을 유도한 Hela 세포가 들어있는 웰의 흡광도(At)를 100%로 하고 IDO 단백질 발현을 유도하지 않은 Hela 세포가 들어있는 웰의 흡광도(Ab)를 0%로 하여 % 흡광도를 계산하였다. (% Absorbance = (A-Ab)/(At-Ab), A = 시험물질을 처리한 웰의 흡광도)Activity was measured using an IDO1 cellular activity quickDetect supplements catalog: #62000-2, BPS Bioscience. Specifically, an assay medium was prepared by diluting IDO1 assay medium substrate 1 (IDO1 assay medium supplement 1) and IDO1 assay medium supplement 2 (IDO1 assay medium supplement 2) in a culture medium at a ratio of 1:100, respectively. Dilute the test substance (compound of each example) in the assay medium by 1/3 from 1 uM to make 10 concentrations, remove the culture medium using a multi-pipet, and then add the assay medium 200 containing the test substance to each well. [mu]l was added and incubated for 24 hours in a 5% carbon dioxide incubator. The next day, 140 μl of the culture medium from each well was transferred to a new 96-well plate, and 10 μl of 6.1N trichloroacetic acid was dispensed into each well, followed by incubation in a 50° C. incubator for 30 minutes. The plate was centrifuged at 2500 rpm for 10 minutes to settle all precipitates. A detection reagent solution (component D kit, catalog: #62000-2, BPS Bioscience) was diluted 50 times in acetic acid to prepare a detection reagent solution. From the centrifuged plate, 100 μl of the supernatant per well was transferred to a new transparent 96-well plate, 100 μl of the assay reagent solution was added to each well, reacted at room temperature for 10 minutes, and absorbance was measured at a wavelength of 480 nm. In the analysis of the results, the absorbance (At) of wells containing Hela cells in which IDO protein expression was induced without treatment with the inhibitor was set to 100%, and the absorbance (Ab) of wells containing Hela cells in which IDO protein expression was not induced was set to 0. The % absorbance was calculated as %. (% Absorbance = (A-Ab)/(At-Ab), A = Absorbance of wells treated with test substance)
상기와 같이 얻어진 시험물질의 50% 억제농도(IC50)를 계산하여 얻어진 결과는 하기 표 1과 같다.The results obtained by calculating the 50% inhibitory concentration (IC 50 ) of the test substance obtained as above are shown in Table 1 below.
시험예 3. IDO1 HEK293 세포 활성 분석Test Example 3. IDO1 HEK293 cell activity assay
세포배양용 96 웰 플레이트(tissue culture-treated 96 well plate)에 배양배지(10% FBS, 페니실린 100 U/ml, 스트렙토마이신 100 ㎍/ml를 함유하는 DMEM) 100 ㎕에 HEK293 세포를 30000 cells/well 접종(seeding)하였다. 5% 이산화탄소 배양기(incubator)에서 24시간 배양 후 리포팩타민2000(Lipofectamine 2000 life technologies #11668027)을 사용하여 IDO1 발현벡터(component A in IDO1 cell-based assay kit catalog#72031 BPS Bioscience)를 형질감염(transfection)시키고, 5% 이산화탄소 배양기에서 24시간 동안 배양하여 IDO1을 발현시켰다.30000 cells/well of HEK293 cells in 100 μl of culture medium (DMEM containing 10% FBS, penicillin 100 U/ml, and
IDO1 세포 기반 분석 키트(IDO1 cell-based assay kit catalog #72031 BPS Bioscience)를 이용하여 활성을 측정하였다. 구체적으로, 배양배지에 IDO1 분석 배지 기질 1(IDO1 assay medium supplement 1)과 IDO1 분석 배지 기질 2(IDO1 assay medium supplement 2)를 각각 1:100 비율로 희석하여 분석 배지(assay medium)를 준비하였다. 분석 배지에 시험 물질(각각의 실시예의 화합물)을 1 uM부터 1/3씩 희석하여 10개 농도로 만들고, 배양배지를 multi-pipet을 이용하여 제거한 후, 각 웰에 시험물질을 포함한 분석 배지 200 ㎕를 넣고 5% 이산화탄소 배양기에서 24시간 배양하였다. 다음날 각 웰에서 140 ㎕의 배양배지를 새로운 96 웰 플레이트에 옮기고, 6.1N 트라이클로로아세트산을 각 웰에 10 ㎕씩 분주한 후, 50℃ 배양기에 30분간 배양하였다. 플레이트를 2500 rpm에서 10분간 원심분리하여 침전물을 모두 가라앉혔다. 아세트산에 측정시약(detection reagent) (component D in IDO1 cell-based assay kit catalog #72031 BPS Bioscience)를 50배 희석하여 측정시약 용액(detection reagent solution)을 제조하였다. 원심분리한 플레이트에서 웰당 100 ㎕의 상등액을 새로운 투명한 96 웰 플레이트에 옮기고, 웰당 100 ㎕의 측정시약 용액을 넣고, 상온에서 10분간 반응시킨 후, 480 nm 파장에서 흡광도를 측정하였다. 결과 분석은 저해제를 처리하지 않고 IDO 단백질 발현시킨 HEK293 세포가 들어있는 웰의 흡광도(At)를 100%로 하고 IDO 단백질 발현 시키지 않은 HEK293 세포가 들어있는 웰의 흡광도(Ab)를 0%로 하여 % 흡광도를 계산하였다. (% Absorbance = (A-Ab)/(At-Ab), A = 시험물질을 처리한 웰의 흡광도)Activity was measured using the IDO1 cell-based assay kit catalog #72031 BPS Bioscience. Specifically, an assay medium was prepared by diluting IDO1 assay medium substrate 1 (IDO1 assay medium supplement 1) and IDO1 assay medium supplement 2 (IDO1 assay medium supplement 2) in a culture medium at a ratio of 1:100, respectively. Dilute the test substance (compound of each example) in the assay medium by 1/3 from 1 uM to make 10 concentrations, remove the culture medium using a multi-pipet, and then add 200 assay medium containing the test substance to each well. [mu]l was added and incubated for 24 hours in a 5% carbon dioxide incubator. The next day, 140 μl of the culture medium from each well was transferred to a new 96-well plate, and 10 μl of 6.1N trichloroacetic acid was dispensed into each well, followed by incubation in a 50° C. incubator for 30 minutes. The plate was centrifuged at 2500 rpm for 10 minutes to settle all precipitates. A detection reagent solution (component D in IDO1 cell-based assay kit catalog # 72031 BPS Bioscience) was diluted 50 times in acetic acid to prepare a detection reagent solution. From the centrifuged plate, 100 μl of the supernatant per well was transferred to a new transparent 96-well plate, 100 μl of the assay reagent solution was added to each well, reacted at room temperature for 10 minutes, and absorbance was measured at a wavelength of 480 nm. For the analysis of the results, the absorbance (At) of the well containing HEK293 cells expressing IDO protein without treatment with the inhibitor was set to 100%, and the absorbance (Ab) of the well containing HEK293 cells without IDO protein expression was set to 0%. Absorbance was calculated. (% Absorbance = (A-Ab)/(At-Ab), A = Absorbance of wells treated with test substance)
상기와 같이 얻어진 시험물질의 50% 억제농도(IC50)를 계산하여 얻어진 결과는 하기 표 1과 같다.The results obtained by calculating the 50% inhibitory concentration (IC 50 ) of the test substance obtained as above are shown in Table 1 below.
(시험예 1)IDO1 enzyme activity
(Test Example 1)
(시험예 2)IDO1 Hela cell activity
(Test Example 2)
(시험예 3)IDO1 Hek293 cell activity
(Test Example 3)
상기 표 1의 결과로부터, 실시예 1 내지 5의 화합물은 인돌아민 2,3-디옥시게나아제 1에 대한 우수한 저해 활성을 나타냄을 알 수 있다.From the results of Table 1, it can be seen that the compounds of Examples 1 to 5 exhibit excellent inhibitory activity against indoleamine 2,3-
시험예 4-1. 정상 랫트에서 경구투여를 통한 약물동태 비교시험 Test Example 4-1. Comparative test of pharmacokinetics through oral administration in normal rats
실시예 1의 화합물과 BMS-986205(대조물질)에 대하여 랫트에서 약물동태를 각각 측정하였다. 실시예 1의 화합물과 BMS-986205(대조물질)을 트윈 80이 0.2% 첨가된 0.5% 메틸셀룰로오스에 현탁시켜 조제한 뒤, 각각 랫트에 10 mg/kg/5 mL 용량으로 경구투여하였다. 소정의 시간에 랫트로부터 혈액 샘플을 채취하고, 각 샘플 중 화합물의 농도를 분석하여 혈중농도 프로파일(plasma concentration profiles)을 얻었으며(도 1a), 이로부터 얻어진 약동학적 파라미터는 다음 표 2와 같다.The pharmacokinetics of the compound of Example 1 and BMS-986205 (control substance) were measured in rats, respectively. The compound of Example 1 and BMS-986205 (control substance) were prepared by suspending them in 0.5% methylcellulose to which 0.2% of
(ng/mL)highest blood level
(ng/mL)
(ng·hr/mL)area under the curve
(ng hr/mL)
(%)bioavailability
(%)
표 2의 결과로부터 알 수 있는 바와 같이, 실시예 1의 화합물은 대조물질(BMS-986205)에 비하여, 정상 랫트에서 각각 3.3 배 및 4.0 배 높은 최고혈중농도 및 혈중 농도 곡선하 면적이 관찰되었으며, 이는 실시예 1의 화합물이 현저하게 높은 체내 노출을 나타냄을 보여준다. 따라서, 실시예 1의 화합물은 BMS-986205보다 동일한 용량에서 현저하게 높은 체내 노출을 나타냄으로써, 우수한 약효를 나타낼 것으로 기대된다. 또한 실시예 1의 화합물은 낮은 용량으로 투여하더라도 BMS-986205와 유사한 체내 노출을 얻을 수 있으므로 우수한 안전성을 나타낼 것으로 기대된다.As can be seen from the results of Table 2, the compound of Example 1 had a peak blood concentration and an area under the blood concentration curve that were 3.3 and 4.0 times higher, respectively, in normal rats than the control substance (BMS-986205), This shows that the compound of Example 1 exhibits a remarkably high in vivo exposure. Therefore, the compound of Example 1 is expected to exhibit excellent pharmacological efficacy by exhibiting significantly higher in vivo exposure at the same dose than BMS-986205. In addition, the compound of Example 1 is expected to exhibit excellent safety because it can obtain a similar in vivo exposure to BMS-986205 even when administered at a low dose.
시험예 4-2. 정상 랫트에서 경구투여를 통한 약물동태 비교시험 Test Example 4-2. Comparative test of pharmacokinetics through oral administration in normal rats
실시예 2 내지 5의 화합물에 대하여 랫트에서 약물동태를 각각 측정하였다. 실시예 2 내지 5의 화합물을 트윈 80이 0.2% 첨가된 0.5% 메틸셀룰로오스에 현탁시켜 조제한 뒤, 각각 랫트에 3 mg/kg/5 mL 용량으로 경구투여하였다. 소정의 시간에 랫트로부터 혈액 샘플을 채취하고, 각 샘플 중 화합물의 농도를 분석하여 혈중농도 프로파일(plasma concentration profiles)을 얻었으며(도 1b), 이로부터 얻어진 약동학적 파라미터는 다음 표 3과 같다.The pharmacokinetics of the compounds of Examples 2 to 5 were measured in rats, respectively. The compounds of Examples 2 to 5 were prepared by suspending them in 0.5% methylcellulose to which 0.2% of
(ng/mL)highest blood level
(ng/mL)
(ng·hr/mL)area under the curve
(ng hr/mL)
(%)bioavailability
(%)
(3mg/kg 투여 환산값)BMS-986205
(Value converted to 3mg/kg dose)
(3mg/kg 투여 환산값)Example 1
(Value converted to 3mg/kg dose)
표 3의 결과로부터 알 수 있는 바와 같이, 실시예 2 내지 5의 화합물은 대조물질(BMS-986205)에 비하여, 정상 랫트에서 각각 1.8배 내지 내지 2.8배 높은 혈중 농도 곡선하 면적이 관찰되었으며, 이는 실시예 2 내지 5의 화합물이 높은 체내 노출을 나타냄을 보여준다. 따라서, 실시예 2 내지 5의 화합물은 BMS-986205보다 동일한 용량에서 유의성 있게 더 높은 체내 노출을 나타냄으로써, 우수한 약효를 나타낼 것으로 기대된다. 또한 실시예 2 내지 5의 화합물은 낮은 용량으로 투여하더라도 BMS-986205와 유사한 체내 노출을 얻을 수 있으므로 우수한 안전성을 나타낼 것으로 기대된다.As can be seen from the results in Table 3, the areas under the blood concentration curves of the compounds of Examples 2 to 5 were 1.8 to 2.8 times higher than those of the control substance (BMS-986205) in normal rats, respectively. It is shown that the compounds of Examples 2 to 5 exhibit high in vivo exposure. Therefore, the compounds of Examples 2 to 5 are expected to exhibit excellent pharmacological efficacy by showing significantly higher in vivo exposure at the same dose than BMS-986205. In addition, the compounds of Examples 2 to 5 are expected to exhibit excellent safety because they can obtain in vivo exposure similar to that of BMS-986205 even when administered at a low dose.
시험예 5-1. 마우스 피하 MC38 종양 모델에서 실시예 1의 화합물 투여에 따른 생체 지표 변화와 약물 동력학 연구Test Example 5-1. Biomarker change and pharmacokinetic study according to administration of the compound of Example 1 in mouse subcutaneous MC38 tumor model
MC38 결장직장암(colorectal) 세포를 피하이식한 C57BL/6 마우스 모델에서 실시예 1의 화합물 투여에 따른 생체 지표 변화와 약물 동력학 연구를 수행하였다. 대조약물로서 BMS-986205을 함께 평가하였다. In a C57BL/6 mouse model subcutaneously implanted with MC38 colorectal cells, changes in biomarkers and pharmacokinetics according to administration of the compound of Example 1 were studied. As a control drug, BMS-986205 was also evaluated.
(1) 세포 배양(1) Cell culture
MC38 종양 세포를 5% CO2 조건에서 37℃에서 10% 열-불활성화된 소 태아 혈청, 2 mM 글루타민, 및 1% 항생제 및 항진균제(antibiotics-antimycotics)이 보충된 DMEM 중에서 단일층 배양하였다. 종양 세포는 트립신-EDTA 처리에 의해 매주 2 회 계대 배양하였다. 약 70-80% 콘플루언시를 유지한 상태에서 계대배양을 실시하였으며, 자동 세포수 계산 장비인 Adam을 이용하여 세포수를 계산 후 1 x 106 세포를 T-75 플라스크에 옮겨 유지 및 배양하였다. 최종적으로, 지수 성장기에 있는 성장하는 세포를 수확하고, 종양 이식을 위해 계수하였다.MC38 tumor cells were monolayer cultured in DMEM supplemented with 10% heat-inactivated fetal bovine serum, 2 mM glutamine, and 1% antibiotics-antimycotics at 37° C. in 5% CO 2 conditions. Tumor cells were subcultured twice a week by trypsin-EDTA treatment. Subculture was performed while maintaining about 70-80% confluency, and after counting the cells using Adam, an automatic cell counting equipment, 1 x 10 6 cells were transferred to a T-75 flask for maintenance and culture did Finally, growing cells in exponential growth phase were harvested and counted for tumor implantation.
(2) 종양 이식 및 동물 그룹화(2) Tumor implantation and animal grouping
각각의 마우스는 종양 발달을 위해 0.1 mL의 PBS 중 MC38 세포(5 x 106 cells)로 우측 상부 옆구리에 피하 이식하였다. 종양 이식 후 약 2주 경과 시점에서 평균 종양 부피가 약 114 mm3에 도달하였을 때, 각 군당 평균 종양 부피가 유사하도록 군분리를 실시하였고, 하기 표 4의 시험 설계에 따라 시험 물질을 1일 및 3일 반복투여 후 0, 2, 12, 14 및 24 시간에 혈액 및 24시간에 종양 조직을 채취하여 약물, 트립토판, 및 키누레닌 농도를 측정하였다.Each mouse was implanted subcutaneously in the right upper flank with MC38 cells (5 x 10 6 cells) in 0.1 mL of PBS for tumor development. When the average tumor volume reached about 114 mm 3 at about 2 weeks after tumor transplantation, group separation was performed so that the average tumor volume in each group was similar, and the test substance was tested according to the test design in Table 4 below. After repeated administration for 3 days, blood at 0, 2, 12, 14 and 24 hours and tumor tissue at 24 hours were collected to measure drug, tryptophan, and kynurenine concentrations.
상기와 같이 1일 및 3일 반복투여 후, 종양 조직에서의 트립토판 및 키누레닌의 농도를 분석한 결과는 하기 표 5와 같고, 혈중 농도 프로파일(plasma concentration profiles)로부터 얻어진 실시예 1의 화합물의 약동력학적 파라미터 및 이로부터 계산된 얻어진 용량 비례성(Dose proportionality) 및 체내 축적(Accumulation)은 표 6과 같다.After repeated administration for 1 day and 3 days as described above, the results of analyzing the concentrations of tryptophan and kynurenine in tumor tissue are shown in Table 5 below, and about the compound of Example 1 obtained from plasma concentration profiles Table 6 shows the kinetic parameters and the resulting dose proportionality and accumulation in the body calculated therefrom.
트립토판
(㎍/g)intratumoral
tryptophan
(μg/g)
키누레닌
(㎍/g)intratumoral
kynurenine
(μg/g)
* 평균, ** BID* mean, ** BID
표 5의 결과로부터 알 수 있는 바와 같이, 실시예 1의 화합물은 1일 투여에 비하여 3일 투여시 투여 농도와 상관없이 현저히 감소된 키누레닌을 나타내었으며, 3일 반복투여시 종양조직에서 현저히 감소된 키누레닌 농도를 나타내었다. 특히, 실시예 1의 화합물 100 mg/kg BID, 3일 반복투여시, 종양조직에서의 키누레닌 농도는 거의 완전히 감소하였다. 또한, 실시예 1의 화합물 투여시 얻어진 혈중 농도 프로파일로부터 얻어진 약동력학적 파라미터는 표 6과 같고, 용량 비례에 비하여 낮은 전신노출도를 나타내었다. 50 mg/kg QD 및 100 mg/kg QD 투여시에는 반복투여에 의한 축적은 거의 관찰되지 않았지만, 100 mg/kg BID 투여시에는 축적(1.7배)이 관찰되었다(표 6).As can be seen from the results in Table 5, the compound of Example 1 exhibited a significantly reduced kynurenine regardless of the dose concentration when administered on the 3rd day compared to the 1-day administration, and significantly decreased in tumor tissues when administered repeatedly on the 3rd day. kynurenine concentration. In particular, when 100 mg/kg BID of the compound of Example 1 was repeatedly administered for 3 days, the concentration of kynurenine in tumor tissues was almost completely reduced. In addition, the pharmacokinetic parameters obtained from the blood concentration profile obtained upon administration of the compound of Example 1 are shown in Table 6, and showed a low systemic exposure compared to the dose proportionality. At the time of administration of 50 mg / kg QD and 100 mg / kg QD, accumulation by repeated administration was hardly observed, but at the time of administration of 100 mg / kg BID, accumulation (1.7 times) was observed (Table 6).
시험예 5-2. 마우스 MC38 종양 피하이식 모델에서 실시예 1 내지 5의 화합물 투여에 따른 바이오마커 변화와 약물동력학 연구Test Example 5-2. Biomarker change and pharmacokinetic study according to administration of the compounds of Examples 1 to 5 in mouse MC38 tumor subcutaneous transplantation model
MC38 결장직장암(colorectal) 세포를 피하이식한 C57BL/6 마우스 모델에서 실시예 1 내지 5의 화합물 투여에 따른 생체 지표 변화와 약물 동력학 연구를 수행하였다. Changes in biomarkers and pharmacokinetics according to administration of the compounds of Examples 1 to 5 were performed in a C57BL/6 mouse model subcutaneously implanted with MC38 colorectal cells.
(1) 세포 배양(1) Cell culture
MC38 종양 세포를 5% CO2 조건에서 37℃에서 10% 열-불활성화된 소 태아 혈청, 2mM 글루타민, 및 1% 항생제 및 항진균제(antibiotics-antimycotics)가 보충된 DMEM 배지 중에서 단일층 배양하였다. 종양 세포는 트립신-EDTA 처리에 의해 매주 2 회 계대배양하였다. 약 70-80% 콘플루언시를 유지한 상태에서 계대배양을 실시하였으며, 자동 세포수 계산 장비인 Adam을 이용하여 세포수를 계산 후 1 x 106 세포를 T-75 플라스크에 옮겨 유지 및 배양하였다. 최종적으로, 지수 성장기에 있는 성장하는 세포를 수확하고, 종양 이식을 위해 계수하였다.MC38 tumor cells were cultured as a monolayer in DMEM medium supplemented with 10% heat-inactivated fetal bovine serum, 2 mM glutamine, and 1% antibiotics-antimycotics at 37° C. under 5% CO 2 conditions. Tumor cells were subcultured twice weekly by trypsin-EDTA treatment. Subculture was performed while maintaining about 70-80% confluency, and after counting the cells using Adam, an automatic cell counting equipment, 1 x 10 6 cells were transferred to a T-75 flask for maintenance and culture did Finally, growing cells in exponential growth phase were harvested and counted for tumor implantation.
(2) 종양 이식 및 시험군 분리(2) Tumor transplantation and test group separation
각각의 마우스는 종양 발달을 위해 0.1 mL의 PBS 중 MC38 세포(5 x 106 cells)로 우측 상부 옆구리에 피하 이식하였다. 종양 이식 후 약 2주 경과 시점에서 평균 종양 부피가 약 171 mm3에 도달하였을 때, 각 군당 평균 종양 부피가 유사하도록 군분리를 실시하였고, 하기 표 7의 시험 설계에 따라 시험 물질을 3일 반복투여 후 0, 2, 4, 8, 14, 및 24 시간에 혈액 및 24시간에 종양 조직을 채취하여 약물, 트립토판, 및 키누레닌 농도를 측정하였다.Each mouse was implanted subcutaneously in the right upper flank with MC38 cells (5 x 10 6 cells) in 0.1 mL of PBS for tumor development. When the average tumor volume reached about 171 mm 3 at about 2 weeks after tumor transplantation, group separation was performed so that the average tumor volume in each group was similar, and the test substance was repeated 3 days according to the test design in Table 7 below. Blood at 0, 2, 4, 8, 14, and 24 hours after administration and tumor tissue at 24 hours were collected to measure drug, tryptophan, and kynurenine concentrations.
상기와 같이 3일 반복투여 후, 혈액 및 종양 조직에서의 트립토판 및 키누레닌의 농도를 분석한 결과는 각각 하기 표 8 및 표 9와 같고, 혈중 농도 프로파일(plasma concentration profiles)로부터 얻어진 실시예 1 내지 5의 화합물의 약동력학적 파라미터는 표 10과 같다.After repeated administration for 3 days as described above, the results of analyzing the concentrations of tryptophan and kynurenine in blood and tumor tissue are shown in Tables 8 and 9 below, respectively, and examples 1 to 10 obtained from plasma concentration profiles The pharmacokinetic parameters of the compound of 5 are shown in Table 10.
트립토판
(μg·hr/mL)blood
tryptophan
(μg hr/mL)
키누레닌
(μg·hr/mL)blood
kynurenine
(μg hr/mL)
트립토판
(㎍/g)intratumoral
tryptophan
(μg/g)
키누레닌
(㎍/g)intratumoral
kynurenine
(μg/g)
* 평균* average
표 8 및 표 9의 결과로부터 알 수 있는 바와 같이, 실시예 1 내지 5의 화합물은 3일 투여시 유사한 정도의 혈중 및 종양조직에서의 키누레닌 감소를 나타내었으며, 우수한 T/P 비율을 나타내었다(표 10).As can be seen from the results of Tables 8 and 9, the compounds of Examples 1 to 5 showed a similar degree of kynurenine reduction in blood and tumor tissues when administered for 3 days, and showed excellent T / P ratios. (Table 10).
시험예 6. 마우스 피하 MC38 종양 모델에서 병용 투여에 따른 항-종양 효능의 생체 내 평가Test Example 6. In vivo evaluation of anti-tumor efficacy according to combined administration in mouse subcutaneous MC38 tumor model
C57BL/6 마우스에서 피하 MC38 결장직장암(colorectal) 모델에서 실시예 1의 화합물과 항-PD-1 항체(Anti-PD-1 antibody, clone RMP1-14 (BE0146), BioXcell사)의 병용 투여에 따른 생체내 항종양 효능을 평가하였다. 대조약물로서 BMS-986205을 함께 평가하였다. MC38 종양 세포는 시험예 5의 (1)과 동일한 방법으로 배양하였다.According to the combined administration of the compound of Example 1 and an anti-PD-1 antibody (Anti-PD-1 antibody, clone RMP1-14 (BE0146), BioXcell) in a subcutaneous MC38 colorectal model in C57BL/6 mice In vivo antitumor efficacy was evaluated. As a control drug, BMS-986205 was also evaluated. MC38 tumor cells were cultured in the same manner as in Test Example 5 (1).
(1) 종양 이식 및 동물 그룹화(1) Tumor implantation and animal grouping
각각의 마우스는 종양 발달을 위해 0.1 mL의 PBS 중 MC38 세포(1 x 106 cells)로 우측 상부 옆구리에 피하 이식하였다. 평균 종양 부피가 대략 50 mm3에 도달했을 때 시험물질 투여를 시작하였다. 각각의 마우스에서 종양발달의 속도는 차이가 있으므로, 종양 부피를 매일 측정하여 50 mm3이 되었을때 개별적으로 시험물질 투여를 실시하였다. 각각의 마우스는 약물투여 시점이 다르므로, 맨 처음 투여일자를 1일차로 하여 진행하였다. 시험 설계의 마우스의 수는 각 그룹당 20마리이다. 그러나, 면역활성화 시험(ex vivo)를 위한 내부 희생을 각 5마리씩 수행하였고 나머지 15마리로 종양성장억제 및 생존률 시험을 실시하였다. 종양이 자라지 않거나 카니발리즘 현상으로 마우스가 죽는 경우, 제외하고 시험을 수행하였다. 시험 물질의 병용 투여에 따른 생체 내 효능 평가를 위한 시험 설계는 하기 표 11과 같다.Each mouse was implanted subcutaneously in the right upper flank with MC38 cells (1 x 10 6 cells) in 0.1 mL of PBS for tumor development. Test substance administration was started when the average tumor volume reached approximately 50 mm 3 . Since the rate of tumor development in each mouse is different, the test substance was administered individually when the tumor volume was measured every day and reached 50 mm 3 . Since each mouse has a different drug administration time point, the first administration date was set as the first day. The number of mice in the test design is 20 for each group. However, internal sacrifice for the immune activation test (ex vivo) was performed for each of 5 rats, and tumor growth inhibition and survival rate tests were performed with the remaining 15 rats. The test was performed except when the tumor did not grow or the mouse died due to cannibalism. The test design for in vivo efficacy evaluation according to the concomitant administration of the test substance is shown in Table 11 below.
(2) 종양 측정 및 종점(2) Tumor measurement and endpoints
종양 부피는 버니어 캘리퍼스를 사용하여 2차원으로 매일 측정하였고, 부피는 하기 식을 사용하여 mm3 으로 계산하였다: Tumor volume was measured daily in two dimensions using vernier calipers, and volume was calculated in mm 3 using the formula:
V (volume) = 0.52a x b2 V (volume) = 0.52axb 2
상기 식에서, a 및 b 는 각각 종양의 긴 직경 및 짧은 직경이다.In the above formula, a and b are the major and minor diameters of the tumor, respectively.
시험계획에 따라 마우스별 종양 부피를 Prism에 입력하였고, 평균값을 계산하였다. 종양 성장 억제에 대한 시험이 끝난 시점인 11일차에 TGI(tumor growth inhibition)를 하기 식을 사용하여 각각의 군에 대해 계산하였다: According to the test plan, the tumor volume of each mouse was input into Prism, and the average value was calculated. At the end of the tumor growth inhibition test, on day 11, TGI (tumor growth inhibition) was calculated for each group using the following formula:
TGI (%) = (Tn-Ti)/Ti x 100TGI (%) = (Tn-Ti)/
상기 식에서, Ti는 11일차의 대조군(비히클 투여군) 마우스의 평균 종양 부피이고, Tn은 11일차의 각 투여군 마우스의 평균 종양 부피이다. 시험 동물은 2,500 mm3의 종양 부피에 도달하였을 때 희생시켰고, 이 종점에 도달하는 시간을 카플란-마이어 (Kaplan-Meier) 생존 분석에 사용하였다.In the above formula, Ti is the average tumor volume of mice of the control group (vehicle-administered group) on day 11, and Tn is the average tumor volume of mice of each administration group on day 11. Test animals were sacrificed when they reached a tumor volume of 2,500 mm 3 , and the time to reach this endpoint was used for Kaplan-Meier survival analysis.
(3) 통계 분석(3) Statistical analysis
군 사이의 종양 부피 차이의 통계 분석을 투여 시작 후 11일째에 시점에서 획득한 데이터에 대해 수행하였다. Two-way ANOVA를 수행하였고, 유의한 F-통계(오차 변이에 대한 치료 변이의 비)를 획득하였을 때, 투키 시험(Tukey’s multiple comparisons test)을 사용하여 군 사이의 비교를 수행하였다. 모든 데이터를 Prism 9.0 을 사용하여 분석하였다. p < 0.05 부터 통계적으로 유의한 것으로 간주하였다: *p<0.05, **p<0.005, ***p<0.0005, ****p<0.0001. Statistical analysis of differences in tumor volume between groups was performed on data obtained at the time point 11 days after start of dosing. Two-way ANOVA was performed, and when a significant F-statistic (ratio of treatment variance to error variance) was obtained, comparisons between groups were performed using Tukey's multiple comparisons test. All data were analyzed using Prism 9.0. Statistically significant was considered from p < 0.05: *p<0.05, **p<0.005, ***p<0.0005, ****p<0.0001.
군 사이의 생존율 차이의 통계 분석을 투여 시작 후 제 50일까지의 생존 데이터에 대해 수행하였다. 카플란-마이어 시험을 수행하였고, 모든 데이터를 GraphPad Prism 9.0 을 사용하여 분석하였고, Log-순위(Log-rank) 시험으로 군 사이 비교를 수행하였으며, p < 0.05 부터 통계적으로 유의한 것으로 간주하였다: *p<0.05, **p<0.005, ***p<0.0005, ****p<0.0001.Statistical analysis of differences in survival rates between groups was performed on survival data up to
(4) 결과(4) Results
MC38 종양 세포가 이식된 C57BL/6 마우스의 각 군의 종양 성장 곡선은 도 2와 같다. 도 3은 11일차의 종양 성장 저해를 나타내는 워터폴 플롯(Waterfall plot)이다. 종양 성장 저해(TGI)는 대조군(비히클 투여군) 마우스의 종양 부피의 평균을 100%으로 하였을 때 각 투여군별 마우스의 평균 종양 부피의 차이를 %로 계산한 값이다. 또한, 11일차의 종양 부피 및 통계 분석 결과는 하기 표 12와 같다.The tumor growth curves of each group of C57BL/6 mice transplanted with MC38 tumor cells are shown in FIG. 2 . Figure 3 is a waterfall plot showing inhibition of tumor growth on day 11. Tumor growth inhibition (TGI) is a value calculated as a percentage of the difference in average tumor volume of mice in each administration group when the average tumor volume of mice in the control group (vehicle administration group) is 100%. In addition, the results of tumor volume and statistical analysis on day 11 are shown in Table 12 below.
+ 항-PD-1 항체 (10 mpk, BIW)BMS-986205 (125 mpk, QD)
+ Anti-PD-1 antibody (10 mpk, BIW)
+ 항-PD-1 항체 (10 mpk, BIW)Compound of Example 1 (50 mpk, BID)
+ Anti-PD-1 antibody (10 mpk, BIW)
+ 항-PD-1 항체 (10 mpk, BIW)Compound of Example 1 (100 mpk, BID)
+ Anti-PD-1 antibody (10 mpk, BIW)
상기 결과로부터 알 수 있는 바와 같이, 대조군(비히클 투여군) 대비 모든 투여군에서 TGI의 정도는 다르지만 유의성 있게 종양 성장을 억제하였다. IDO 저해제와 항-PD-1항체의 병용 투여군은 통계적으로 유의성 있는 종양 성장에 대한 억제 를 나타내었다(각 군에 대하여, p<0.0001). 특히 실시예 1의 화합물(100 mpk, BID)과 항-PD-1 항체의 병용 투여군은 86.7%의 현저하게 높은(즉, 상승적인) 종양 성장에 대한 억제 활성을 나타내었으며, 다른 군에 비하여 뚜렷하게 감소된 종양 부피를 보여주었다(**** P < 0.0001).As can be seen from the above results, although the degree of TGI was different in all administration groups compared to the control group (vehicle administration group), tumor growth was significantly inhibited. The group administered with the IDO inhibitor and anti-PD-1 antibody showed statistically significant inhibition of tumor growth (p<0.0001 for each group). In particular, the combination administration group of the compound of Example 1 (100 mpk, BID) and the anti-PD-1 antibody showed a remarkably high (i.e., synergistic) tumor growth inhibitory activity of 86.7%, significantly compared to the other groups. showed reduced tumor volume (**** P < 0.0001).
도 4는 MC38 종양을 갖는 C57BL/6 마우스의 각 처리군의 생존 곡선을 나타낸다. 동물은 종양 부피가 2,500 mm3를 초과하여 도달하였을 때 희생시켰다. 도 4의 결과로부터, 대조군(비히클 투여군)에 대한 각 처리군의 생존 곡선의 통계 분석 결과는 하기 표 13과 같다. Log-순위(Log-rank) 시험을 사용하여, 대조군(비히클 투여군)에 대하여 각 처리군의 비교를 수행하였다.Figure 4 shows the survival curves of each treatment group of C57BL/6 mice bearing MC38 tumors. Animals were sacrificed when tumor volumes reached greater than 2,500 mm 3 . From the results of FIG. 4, the statistical analysis results of the survival curves of each treatment group relative to the control group (vehicle administration group) are shown in Table 13 below. Comparison of each treatment group with respect to the control group (vehicle administration group) was performed using a log-rank test.
(일수)median survival
(number of days)
+ 항-PD-1 항체 (10 mpk, BIW)BMS-986205 (125 mpk, QD)
+ Anti-PD-1 antibody (10 mpk, BIW)
+ 항-PD-1 항체 (10 mpk, BIW)Compound of Example 1 (50 mpk, BID)
+ Anti-PD-1 antibody (10 mpk, BIW)
+ 항-PD-1 항체 (10 mpk, BIW)Compound of Example 1 (100 mpk, BID)
+ Anti-PD-1 antibody (10 mpk, BIW)
표 13의 결과로부터 알 수 있는 바와 같이, 대조군(비히클 투여군)과 비교하여, 항-PD-1항체 단독 투여군, BMS-986205 (125 mpk, QD) 단독 투여군과 항-PD-1 항체 병용 투여군, 실시예 1의 화합물(50 mpk, BID / 100 mpk, BID) 단독 투여군 및 항-PD-1 항체 병용 투여군 모두 시험 동물의 생존율을 유의적으로 연장시켰다(p<0.0001).As can be seen from the results of Table 13, compared to the control group (vehicle administration group), the anti-PD-1 antibody alone administration group, the BMS-986205 (125 mpk, QD) alone administration group and the anti-PD-1 antibody combination administration group, Both the group administered with the compound of Example 1 (50 mpk, BID / 100 mpk, BID) alone and the group administered with the anti-PD-1 antibody significantly extended the survival rate of the test animals (p<0.0001).
또한, Log-순위(Log-rank) 시험을 사용하여, 항-PD-1 항체 투여군에 대한 각 군의 생존 곡선의 통계 분석 결과는 하기 표 14와 같다.In addition, the statistical analysis results of the survival curves of each group for the anti-PD-1 antibody administration group using the Log-rank test are shown in Table 14 below.
(일수)median survival
(number of days)
+ 항-PD-1 항체(10 mpk, BIW)BMS-986205 (125 mpk, QD)
+ anti-PD-1 antibody (10 mpk, BIW)
+ 항-PD-1 항체(10 mpk, BIW)Compound of Example 1 (50 mpk, BID)
+ anti-PD-1 antibody (10 mpk, BIW)
+ 항-PD-1 항체(10 mpk, BIW)Compound of Example 1 (100 mpk, BID)
+ anti-PD-1 antibody (10 mpk, BIW)
표 14의 결과로부터 알 수 있는 바와 같이, BMS-986205 (125 mpk, QD)와 항-PD-1 항체 병용 투여는 시험 동물의 생존율을 연장시키지 못하였다(p=0.2813). 이에 반하여, 실시예 1의 화합물(50 mpk, BID / 100 mpk, BID)과 항-PD-1 항체 병용 투여는 시험 동물의 생존율을 시험 동물의 생존율을 유의하게 연장시켰다(각각 p=0.0008, p<0.0001). 또한 시험물질 투여 50일차에서의 무종양 마우스에 있어서, 실시예 1의 화합물(50 mpk, BID)과 항-PD-1 항체의 병용 투여군은 14마리 개체중 2마리가 완전 관해(Complete Response, CR)를 나타내었고, 실시예 1의 화합물(100 mpk, BID)과 항-PD-1 항체의 병용 투여군은 15마리 개체중 5마리가 완전 관해(CR)를 나타내었다.As can be seen from the results in Table 14, the combined administration of BMS-986205 (125 mpk, QD) and anti-PD-1 antibody did not prolong the survival rate of the test animals (p=0.2813). In contrast, the combined administration of the compound of Example 1 (50 mpk, BID / 100 mpk, BID) and the anti-PD-1 antibody significantly prolonged the survival rate of the test animals (each p = 0.0008, p <0.0001). In addition, in the tumor-free mice on the 50th day of administration of the test substance, in the group administered with the compound of Example 1 (50 mpk, BID) and the anti-PD-1 antibody in combination, 2 out of 14 subjects had complete response (Complete Response, CR). ), and in the group administered with the compound of Example 1 (100 mpk, BID) and the anti-PD-1 antibody in combination, 5 out of 15 subjects showed complete remission (CR).
또한, Log-순위(Log-rank) 시험을 사용하여, 실시예 1의 화합물(100 mpk, BID) 단독 투여군에 대한 실시예 1의 화합물(100 mpk, BID)과 항-PD-1 항체의 병용 투여군에 대한 생존 곡선의 통계 분석 결과는 하기 표 15와 같다.In addition, using the Log-rank test, the combination of the compound of Example 1 (100 mpk, BID) and the anti-PD-1 antibody for the compound of Example 1 (100 mpk, BID) alone administration group Statistical analysis results of survival curves for the administration groups are shown in Table 15 below.
(일수)median survival
(number of days)
+ 항-PD-1 항체(10 mpk, BIW)Compound of Example 1 (100 mpk, BID)
+ anti-PD-1 antibody (10 mpk, BIW)
표 15의 결과로부터 알 수 있는 바와 같이, 실시예 1의 화합물(100 mpk, BID) 단독 투여군과 비교하였을 때, 실시예 1의 화합물(100 mpk, BID)과 항-PD-1 항체를 병용하여 투여하였을 때 유의성 있게 높은 항-종양 효과를 나타내었으며, 시험 동물의 생존율을 유의성 있게 연장시켰다(p<0.0001). 시험물질 투여 50일차에서의 무종양 마우스에 있어서, 실시예 1의 화합물(100 mpk, BID) 단독 투여군은 13마리 개체중 1마리가 완전 관해(CR)를 나타내었음에 반해, 실시예 1의 화합물(100 mpk, BID)과 항-PD-1 항체의 병용 투여군은 15마리 개체중 5마리가 완전 관해(CR)를 나타내었다.As can be seen from the results of Table 15, compared to the group administered with the compound of Example 1 (100 mpk, BID) alone, the combination of the compound of Example 1 (100 mpk, BID) and the anti-PD-1 antibody When administered, it showed a significantly high anti-tumor effect and significantly extended the survival rate of test animals (p<0.0001). In tumor-free mice on the 50th day of administration of the test substance, in the group administered with the compound of Example 1 (100 mpk, BID) alone, 1 out of 13 subjects showed complete remission (CR), whereas the compound of Example 1 showed complete remission (CR). (100 mpk, BID) and the anti-PD-1 antibody combined administration group, 5 out of 15 subjects showed complete remission (CR).
도 5a 내지 도 5c는 생존한 개체들 중 완전 관해를 보인 개체들의 종양 부피 추적 곡선을 나타낸다. 도 5a 내지 도 5c의 결과로부터 알 수 있는 바와 같이, 약물 투여가 중단된 이후에도 종양 재발(tumor recurrence)은 발생하지 않았다.5A to 5C show tumor volume tracing curves of individuals who showed complete remission among surviving individuals. As can be seen from the results of FIGS. 5A to 5C , tumor recurrence did not occur even after drug administration was stopped.
상기 결과로부터, 실시예 1의 화합물과 항-PD-1 항체의 병용 투여는 MC38 결장직장암 동물 모델에서 뚜렷한 상승적인 항종양 활성을 나타내었고, 동물의 생존율을 현저하게 연장시켰음을 확인할 수 있다.From the above results, it can be confirmed that the combined administration of the compound of Example 1 and the anti-PD-1 antibody showed a clear synergistic antitumor activity in the MC38 colorectal cancer animal model and significantly extended the survival rate of the animal.
Claims (16)
<화학식 1>
식 중,
R1은 C1∼C6 알킬기이고,
A는 벤조[d]옥사졸일 및 퀴나졸린일로 이루어진 군으로부터 선택된 헤테로아릴기이고, 상기 헤테로아릴기는 할로겐 및 C1∼C6 알킬로 이루어진 군으로부터 선택된 1개 또는 2개의 치환기로 치환된다.Prevention of cancer comprising a combination of a first compartment containing the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient and a second compartment containing an immune checkpoint inhibitor as an active ingredient or a pharmaceutical composition for treatment.
<Formula 1>
during the ceremony,
R 1 is a C 1 -C 6 alkyl group;
A is a heteroaryl group selected from the group consisting of benzo[d]oxazolyl and quinazolinyl, and the heteroaryl group is substituted with one or two substituents selected from the group consisting of halogen and C 1 -C 6 alkyl.
6-클로로-N-((R)-1-((시스)-4-(6-플루오로퀴놀린-4-일)사이클로헥실)프로판-2-일)벤조[d]옥사졸-2-아민;
6-클로로-N-((R)-1-((시스)-4-(6-플루오로퀴놀린-4-일)싸이클로헥실)부탄-2-일)벤조[d]옥사졸-2-아민;
6-플루오로-N-((R)-1-((시스)-4-(6-플루오로퀴놀린-4-일)사이클로헥실)프로판-2-일)벤조[d]옥사졸-2-아민;
6,7-다이플루오로-N-((R)-1-((시스)-4-(6-플루오로퀴놀린-4-일)사이클로헥실)프로판-2-일)벤조[d]옥사졸-2-아민; 및
2-클로로-N-((R)-1-((시스)-4-(6-플루오로퀴놀린-4-일)사이클로헥실)프로판-2-일)-7-메틸퀴나졸린-4-아민
으로 이루어진 군으로부터 선택되는 것을 특징으로 하는 약학 조성물.The method of claim 1, wherein the compound of formula 1
6-chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazol-2-amine ;
6-chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)butan-2-yl)benzo[d]oxazol-2-amine ;
6-fluoro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazol-2- amine;
6,7-difluoro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole -2-amine; and
2-chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-7-methylquinazolin-4-amine
A pharmaceutical composition, characterized in that selected from the group consisting of.
<화학식 1>
식 중,
R1은 C1∼C6 알킬기이고,
A는 벤조[d]옥사졸일 및 퀴나졸린일로 이루어진 군으로부터 선택된 헤테로아릴기이고, 상기 헤테로아릴기는 할로겐 및 C1∼C6 알킬로 이루어진 군으로부터 선택된 1개 또는 2개의 치환기로 치환된다.A method for treating cancer comprising administering to a mammal a therapeutically effective amount of a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of an immune checkpoint inhibitor.
<Formula 1>
during the ceremony,
R 1 is a C 1 -C 6 alkyl group;
A is a heteroaryl group selected from the group consisting of benzo[d]oxazolyl and quinazolinyl, and the heteroaryl group is substituted with one or two substituents selected from the group consisting of halogen and C 1 -C 6 alkyl.
6-클로로-N-((R)-1-((시스)-4-(6-플루오로퀴놀린-4-일)사이클로헥실)프로판-2-일)벤조[d]옥사졸-2-아민;
6-클로로-N-((R)-1-((시스)-4-(6-플루오로퀴놀린-4-일)싸이클로헥실)부탄-2-일)벤조[d]옥사졸-2-아민;
6-플루오로-N-((R)-1-((시스)-4-(6-플루오로퀴놀린-4-일)사이클로헥실)프로판-2-일)벤조[d]옥사졸-2-아민;
6,7-다이플루오로-N-((R)-1-((시스)-4-(6-플루오로퀴놀린-4-일)사이클로헥실)프로판-2-일)벤조[d]옥사졸-2-아민; 및
2-클로로-N-((R)-1-((시스)-4-(6-플루오로퀴놀린-4-일)사이클로헥실)프로판-2-일)-7-메틸퀴나졸린-4-아민
으로 이루어진 군으로부터 선택되는 것을 특징으로 하는 치료 방법.10. The method of claim 9, wherein the compound of Formula 1 is
6-chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazol-2-amine ;
6-chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)butan-2-yl)benzo[d]oxazol-2-amine ;
6-fluoro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazol-2- amine;
6,7-difluoro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)benzo[d]oxazole -2-amine; and
2-chloro-N-((R)-1-((cis)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propan-2-yl)-7-methylquinazolin-4-amine
A treatment method, characterized in that selected from the group consisting of.
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