KR102582097B1 - Janus kinase inhibitors and use thereof - Google Patents
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- KR102582097B1 KR102582097B1 KR1020220186966A KR20220186966A KR102582097B1 KR 102582097 B1 KR102582097 B1 KR 102582097B1 KR 1020220186966 A KR1020220186966 A KR 1020220186966A KR 20220186966 A KR20220186966 A KR 20220186966A KR 102582097 B1 KR102582097 B1 KR 102582097B1
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Abstract
본 발명은 야누스키나아제 표적 억제제 (Janus kinase inhibitors; JAKi) 및 이의 용도에 관한 것으로, 본 발명의 화합물은 JAK 활성을 효과적으로 억제하여 우수한 JAK/STATs 신호전달 억제 효능을 가져, 비정상적 JAK/STATs 신호전달로 말미암아 발생하는 질환으로써 염증성 자가면역질환 및 암을 효과적으로 개선 또는 치료할 수 있다.The present invention relates to Janus kinase inhibitors (JAKi) and their uses. The compounds of the present invention effectively inhibit JAK activity and have excellent JAK/STATs signaling inhibition efficacy, thereby preventing abnormal JAK/STATs signaling. As a result, inflammatory autoimmune diseases and cancer can be effectively improved or treated.
Description
본 발명은 야누스키나아제 표적 억제제 (Janus kinase inhibitors; JAKi) 및 이의 용도에 관한 것이다.The present invention relates to Janus kinase inhibitors (JAKi) and uses thereof.
야누스 키나아제 (Janus kinase; JAK)는 세포내 비수용체 티로신 인산화효소 패밀리 (non-receptor tyrosine kinase family)로 사이토카인에 의하여 유도된 신호를 JAK/STAT 신호전달경로를 통하여 전달하여 면역, 세포분열, 세포사멸 및 종양 형성과 같은 과정에 관여한다 (본 발명에서 'JAK/STATs'는 'JAK 및 STATs'와 동일한 의미임). JAK/STATs 신호전달에는 수용체 (사이토카인과 같은 리간드와 결합), 야누스 키나아제 (Janus Kinases, JAKs), 신호 변환기 및 전사 단백질 활성화제 (signal transducer and activator of transcription proteins; STATs) 등의 세 가지 주요 요소가 관여한다.Janus kinase (JAK) is an intracellular non-receptor tyrosine kinase family that transmits signals induced by cytokines through the JAK/STAT signaling pathway to regulate immunity, cell division, and cell division. Involved in processes such as apoptosis and tumorigenesis (in the present invention, 'JAK/STATs' has the same meaning as 'JAK and STATs'). JAK/STATs signaling has three main components: receptors (which bind ligands such as cytokines), Janus Kinases (JAKs), and signal transducers and activators of transcription proteins (STATs). is involved.
이 경로는 세포 외부의 화학신호(정보)를 세포핵으로 전달하여 전사과정을 통해 유전자를 활성화한다. 즉, 다양한 리간드, 일반적으로 인터페론 및 인터루킨과 같은 사이토카인이 세포 표면 수용체에 결합하면 수용체가 이합체화(dimerization)되어 수용체 관련 JAK가 근접하게 된다. 이후, JAK는 활성화 루트라고 하는 영역에 위치한 티로신 잔기에서 서로를 인산화한다. 이 과정은 인산화 전이(transphosphorylation)라는 과정을 통해 키나아제 도메인의 활성을 증가시킨다. 활성화된 JAK는 수용체의 티로신 잔기를 인산화하여 SH2 도메인을 소유한 단백질의 결합부위를 생성한다. 이후, STAT는 SH2 도메인을 사용하여 수용체의 인산화된 티로신에 결합한 다음 JAK에 의해 티로신 잔기가 인산화되어 STAT가 수용체에서 분리되도록 한다. 이러한 활성화된 STAT는 이종이량체(homo-dimerization) 또는 동종이량체(hetero-dimerization)를 형성하는데, 여기서 각 STAT의 SH2 도메인은 반대쪽 STAT의 인산화된 티로신 잔기와 결합한 다음 이량체(dimer)가 세포핵으로 이동하여 표적 유전자의 전사를 유도한다. STAT는 또한 수용체 티로신 키나아제에 의해 직접 티로신 인산화될 수 있다. 그러나 대부분의 수용체에는 내장된 키나아제 활성이 없기 때문에 일반적으로 신호 전달에 JAK가 필요하다.This pathway transmits chemical signals (information) from outside the cell to the cell nucleus and activates genes through the transcription process. That is, when various ligands, typically cytokines such as interferons and interleukins, bind to cell surface receptors, the receptors dimerize, bringing the receptor-associated JAKs into proximity. Afterwards, JAKs phosphorylate each other at tyrosine residues located in a region called the activation route. This process increases the activity of the kinase domain through a process called transphosphorylation. Activated JAKs phosphorylate tyrosine residues on the receptor, creating a binding site for proteins possessing an SH2 domain. Afterwards, the STAT uses its SH2 domain to bind to the phosphorylated tyrosine of the receptor, and then the tyrosine residue is phosphorylated by JAK, causing the STAT to dissociate from the receptor. These activated STATs form homo-dimerization or hetero-dimerization, in which the SH2 domain of each STAT binds to the phosphorylated tyrosine residue of the opposite STAT and the dimer then enters the cell nucleus. to induce transcription of the target gene. STATs can also be directly tyrosine phosphorylated by receptor tyrosine kinases. However, because most receptors do not have built-in kinase activity, JAKs are generally required for signal transduction.
JAK/STATs 신호는 동물 발달에서 중요한 역할을 하는데, 이 경로는 분화 뿐만 아니라 혈액 세포의 분열과 성장을 촉진할 수 있어, 인간과 생쥐의 과도한 백혈구 분열과 관련이 있다. 또한, JAK/STATs 경로는 세포사멸, 염증 및 암과 같은 많은 기본 과정에서 중요한 역할을 하기 때문에 경로에서 비정상적으로 활성화된 단백질은 여러 질병을 유발할 수 있다. 일 예로 JAK/STATs 신호의 변화는 중증 복합 면역결핍 장애(SCID)와 같은 면역 체계에 영향을 미치는 다양한 종류의 암 및 염증성 면역질환을 유발할 수 있다.JAK/STATs signaling plays an important role in animal development, as this pathway can promote division and growth of blood cells as well as differentiation, and is associated with excessive leukocyte division in humans and mice. Additionally, because the JAK/STATs pathway plays an important role in many basic processes such as apoptosis, inflammation, and cancer, abnormally activated proteins in the pathway can cause several diseases. For example, changes in JAK/STATs signaling can cause various types of cancer and inflammatory immune diseases that affect the immune system, such as severe combined immunodeficiency disorder (SCID).
본 발명의 목적은 하기 화학식 1 또는 2의 구조를 갖는 JAK을 표적으로 하는 JAK/STATs 신호전달 억제제 및 이의 용도를 제공하는 것이다. The purpose of the present invention is to provide a JAK/STATs signaling inhibitor targeting JAK having the structure of Formula 1 or 2 below and its use.
[화학식 1][Formula 1]
[화학식 2][Formula 2]
본 발명은 하기 화학식 1 또는 화학식 2의 구조를 가지는 화합물을 유효성분으로 포함하되,The present invention includes a compound having the structure of Formula 1 or Formula 2 below as an active ingredient,
[화학식 1][Formula 1]
[화학식 2][Formula 2]
상기 화학식 1 및 화학식 2의 R1은 -CH3, -C(CH3)3, -(CH2)n-CH3 (n은 1-5), 페닐기(phenyl group), 이소프로필기(isopropyl group), 사이클로헥실기(cyclohexyl group), 사이클로펜탄기(cyclopentane group), 사이클로펜타디엔기(cyclopentadiene group), 메틸사이클로펜타디엔기(methyl cyclopentadiene group) 중 선택되는 어느 하나이며,R1 in Formulas 1 and 2 is -CH 3 , -C(CH 3 ) 3 , -(CH 2 )n-CH 3 (n is 1-5), a phenyl group, and an isopropyl group. ), a cyclohexyl group, a cyclopentane group, a cyclopentadiene group, or a methyl cyclopentadiene group,
상기 화학식 1 및 화학식 2의 R2는 시아노기(cyano group)인, JAK/STATs 신호전달 억제제를 제공한다.R2 in Formulas 1 and 2 is a cyano group, providing a JAK/STATs signaling inhibitor.
한편, 본 발명은 상기의 JAK을 표적으로 하는 JAK/STATs 신호전달 억제제를 포함하는 비정상적 JAK/STATs 신호전달로 말미암아 발생하는 질환의 예방 또는 치료용 약학 조성물을 제공한다.Meanwhile, the present invention provides a pharmaceutical composition for preventing or treating diseases caused by abnormal JAK/STATs signaling, including the JAK/STATs signaling inhibitor targeting the above JAKs.
본 발명의 약학 조성물에 있어, 상기 비정상적 JAK/STATs 신호전달로 말미암아 발생하는 질환은, 바람직하게는 염증성 자가면역질환 또는 암이다.In the pharmaceutical composition of the present invention, the disease caused by abnormal JAK/STATs signaling is preferably an inflammatory autoimmune disease or cancer.
이때, 상기 염증성 자가면역질환은, 일 예로 류마티스 관절염, 루푸스, 다발성 경화증, 건선, 염증성 대장염, 궤양성 대장염, 크론병, 탈모, 쇼그렌 증후군, 베체트병, 강직성 척추염, 제1형 당뇨병, 백반증, 피부근염, 경피증, 섬유조직염, IgA 신염 중 선택되는 어느 하나일 수 있다.At this time, the inflammatory autoimmune diseases include, for example, rheumatoid arthritis, lupus, multiple sclerosis, psoriasis, inflammatory colitis, ulcerative colitis, Crohn's disease, hair loss, Sjögren's syndrome, Behçet's disease, ankylosing spondylitis, type 1 diabetes, vitiligo, skin It may be any one selected from myositis, scleroderma, fibrositis, and IgA nephritis.
이때, 상기 암은, 일 예로 고형암 및 혈액암을 모두 포함하는 것일 수 있다.At this time, the cancer may include, for example, both solid cancer and hematological cancer.
한편, 본 발명은 상기의 JAK을 표적으로 하는 JAK/STATs 신호전달 억제제를 포함하는 비정상적 JAK/STATs 신호전달로 말미암아 발생하는 질환의 개선용 식품 조성물을 제공한다.Meanwhile, the present invention provides a food composition for improving diseases caused by abnormal JAK/STATs signaling, including the JAK/STATs signaling inhibitor targeting the above JAK.
이때, 상기 비정상적 JAK/STATs 신호전달로 말미암아 발생하는 질환은, 일 예로 염증성 자가면역질환 또는 암일 수 있다. At this time, the disease caused by the abnormal JAK/STATs signaling may be, for example, an inflammatory autoimmune disease or cancer.
이때, 상기 염증성 자가면역질환은, 일 예로 류마티스 관절염, 루푸스, 다발성 경화증, 건선, 염증성 대장염, 궤양성 대장염, 크론병, 탈모, 쇼그렌 증후군, 베체트병, 강직성 척추염, 제1형 당뇨병, 백반증, 피부근염, 경피증, 섬유조직염, IgA 신염 중 선택되는 어느 하나일 수 있다.At this time, the inflammatory autoimmune diseases include, for example, rheumatoid arthritis, lupus, multiple sclerosis, psoriasis, inflammatory colitis, ulcerative colitis, Crohn's disease, hair loss, Sjögren's syndrome, Behçet's disease, ankylosing spondylitis, type 1 diabetes, vitiligo, skin It may be any one selected from myositis, scleroderma, fibrositis, and IgA nephritis.
이때, 상기 암은, 일 예로 고형암 및 혈액암을 포함하는 것일 수 있다.At this time, the cancer may include, for example, solid cancer and blood cancer.
본 발명의 화합물은 우수한 JAKs 표적 억제에 의한 JAK/STATs 신호전달 억제 효능을 가져, 비정상적 JAK/STATs 신호전달로 말미암아 발생하는 질환으로써 염증성 자가면역질환 및 암을 효과적으로 개선 또는 치료할 수 있다.The compound of the present invention has an excellent effect of inhibiting JAK/STATs signaling by inhibiting JAKs targets, and can effectively improve or treat inflammatory autoimmune diseases and cancer, which are diseases caused by abnormal JAK/STATs signaling.
실질적으로, JAK/STATs 신호와 자가면역질환 및 암과의 연관성이 밀접하다고 알려진 만큼 특정 화합물의 JAK 신호 및 STATs 억제 효능만을 확인하여도, 해당 화합물이 염증성 자가면역질환 및 암의 치료제로써 이용될 수 있고, 실제로 JAK/STATs 신호 억제 효능을 확인한 화합물들이 약물로서 승인받은 바 있다.In fact, as it is known that JAK/STATs signaling is closely related to autoimmune diseases and cancer, even if only the efficacy of JAK signaling and STATs inhibition of a specific compound is confirmed, the compound can be used as a treatment for inflammatory autoimmune diseases and cancer. In fact, compounds that have confirmed the efficacy of inhibiting JAK/STATs signaling have been approved as drugs.
일 예로, 젤잔즈정 및 올루미언트정은 JAK 억제제로서 류마티스 관절염 등의 치료제로 시판되고 있고, 룩소리티닙정은 JAK1 및 JAK2에 선택성을 갖는 억제제로서 골수 증식 장애의 일종인 중간 또는 고위험 골수 섬유증의 치료를 위해 시판되고 있다.For example, Xeljanz tablets and Olumiant tablets are JAK inhibitors and are marketed as treatments for rheumatoid arthritis, etc., and ruxolitinib tablets are selective inhibitors for JAK1 and JAK2 and are used to treat intermediate or high-risk myelofibrosis, a type of myeloproliferative disorder. It is being marketed for.
또한, 토파시티닙을 성분으로 하는 젤잔즈는 JAK1 및 JAK3 억제제로서 건선 및 류마티스 관절염 치료제로 시판되고 있으며, 최근 크론병 및 궤양성 대장염 치료제로도 승인받았다.In addition, Xeljanz, which contains tofacitinib, is a JAK1 and JAK3 inhibitor and is marketed as a treatment for psoriasis and rheumatoid arthritis, and was recently approved as a treatment for Crohn's disease and ulcerative colitis.
한편, STAT3를 표적으로 하는 치료법이 암 환자의 생존율을 향상시킬 수 있다는 보고하에 JW 중외제약에서는 STAT3 억제제인 JW2286를 표적 항암제로서 이용하기 위하여 신약개발에 착수한 바 있다.Meanwhile, under the report that treatment targeting STAT3 can improve the survival rate of cancer patients, JW Jungwae Pharmaceutical has begun developing a new drug to use JW2286, a STAT3 inhibitor, as a targeted anticancer drug.
도 1은 본 발명에 따른 화합물의 STAT92E 활성 억제능을 평가한 결과이다.
도 2는 본 발명에 따른 화합물의 JAK/STAT 활성 억제능을 평가한 결과이다.
도 3은 본 발명에 따른 화합물의 JAK 동질효소(isozyme)의 키나아제(kinase) 부위 서열 유사성 및 결합 부위 유사성을 확인한 결과이다.
도 4는 본 발명에 따른 화합물의 JAK 동질효소(isozyme)의 키나아제 도메인(kinase domain)과의 결합 부위를 분석한 결과이다.Figure 1 shows the results of evaluating the ability of compounds according to the present invention to inhibit STAT92E activity.
Figure 2 shows the results of evaluating the JAK/STAT activity inhibition ability of the compound according to the present invention.
Figure 3 shows the results of confirming the sequence similarity and binding site similarity of the JAK isozyme of the compound according to the present invention.
Figure 4 shows the results of analyzing the binding site of the compound according to the present invention with the kinase domain of the JAK isozyme.
하기에서는 중복되는 내용의 혼잡을 방지하기 위하여, 중복되는 내용의 기재를 생략하고자 하였다. 즉, 하기의 내용만으로 발명의 내용이 한정되는 것은 아니고, 전체적인 발명의 내용에 따라 발명의 내용이 해석되어야 할 것이다.In the following, in order to prevent confusion with overlapping content, description of overlapping content has been omitted. In other words, the content of the invention is not limited to the following content, and the content of the invention should be interpreted according to the overall content of the invention.
본 발명은 하기 화학식 1 또는 화학식 2의 구조를 가지는 화합물을 유효성분으로 포함하되,The present invention includes a compound having the structure of Formula 1 or Formula 2 below as an active ingredient,
[화학식 1][Formula 1]
[화학식 2][Formula 2]
상기 화학식 1 및 화학식 2의 R1은 -CH3, -C(CH3)3, -(CH2)n-CH3 (n은 1-5), 페닐기(phenyl group), 이소프로필기(isopropyl group), 사이클로헥실기(cyclohexyl group), 사이클로펜탄기(cyclopentane group), 사이클로펜타디엔기(cyclopentadiene group), 메틸사이클로펜타디엔기(methyl cyclopentadiene group) 중 선택되는 어느 하나이며,R1 in Formulas 1 and 2 is -CH 3 , -C(CH 3 ) 3 , -(CH 2 )n-CH 3 (n is 1-5), a phenyl group, and an isopropyl group. ), a cyclohexyl group, a cyclopentane group, a cyclopentadiene group, or a methyl cyclopentadiene group,
상기 화학식 1 및 화학식 2의 R2는 시아노기(cyano group)인, JAK을 표적으로 하는 JAK/STATs 신호전달 억제제를 제공한다.R2 of Formulas 1 and 2 is a cyano group, providing a JAK/STATs signaling inhibitor targeting JAK.
본 발명의 실시예에서는 본 발명에 따른 화합물(상기의 화학식 1 및 2)과 JAK 패밀리 단백질 (JAK1, JAK2, JAK3, TYK3) 간의 결합 모델을 분석하여 보았는데, 그 결과 본 발명에 따른 화합물의 R1 부분은 JAK 패밀리 단백질의 키나아제 포켓 (kinase pocket) 내에서 소수성 결합을 통한 결합 구조의 안정화에 기여를 하는 것으로 추론되었다. 다만, R1 부분의 분자량이 너무 크면 오히려 구조의 안정성을 해칠 수 있으므로, 상기 화학식 1 및 화학식 2의 R1 위치에는, -CH3, -C(CH3)3, -(CH2)n-CH3 (n은 1-5), 페닐기(phenyl group), 이소프로필기(isopropyl group), 사이클로헥실기(cyclohexyl group), 사이클로펜탄기(cyclopentane group), 사이클로펜타디엔기(cyclopentadiene group), 메틸사이클로펜타디엔기(methyl cyclopentadiene group) 중 선택되는 어느 하나의 소수성 그룹이 위치할 수 있다. In an example of the present invention, the binding model between the compound according to the present invention (Formula 1 and 2 above) and JAK family proteins (JAK1, JAK2, JAK3, TYK3) was analyzed, and as a result, the R1 portion of the compound according to the present invention It was inferred that it contributes to the stabilization of the binding structure through hydrophobic bonds within the kinase pocket of JAK family proteins. However, if the molecular weight of the R1 portion is too large, the stability of the structure may be impaired. Therefore, at the R1 position in Formulas 1 and 2, -CH 3 , -C(CH 3 ) 3 , -(CH 2 )n-CH 3 (n is 1-5), phenyl group, isopropyl group, cyclohexyl group, cyclopentane group, cyclopentadiene group, methylcyclopenta Any one hydrophobic group selected from a diene group (methyl cyclopentadiene group) may be located.
한편, R2에는 시아노기(cyano group)가 위치하는데 시아노기의 질소원자는 비공유 전자쌍을 가지고 있는 반응성이 높은 작용기로서, 이 부분은 JAK 패밀리 단백질의 키나아제 도메인 (kinase domain)에 존재하는 반응성이 높은 친수성 부분과 상호 작용을 하여, 본 발명의 화합물이 JAK을 표적으로 하여 JAK/STATs 신호전달 억제제로 역할을 수행하게 한다.Meanwhile, a cyano group is located in R2, and the nitrogen atom of the cyano group is a highly reactive functional group with a lone pair of electrons, and this portion is a highly reactive hydrophilic portion present in the kinase domain of JAK family proteins. By interacting with, the compound of the present invention targets JAK and acts as a JAK/STATs signaling inhibitor.
한편, 일부 특정한 구현예에서, 본 개시사항의 화합물은 일반식 1의 화합물 또는 이의 이성질체, 약학적으로 허용가능한 염, 용매화물, 결정, 등배전자체 또는 전구약물이다.Meanwhile, in some specific embodiments, the compounds of the present disclosure are compounds of Formula 1 or an isomer, pharmaceutically acceptable salt, solvate, crystal, isosteron, or prodrug thereof.
또한, 일부 특정한 구현예에서, 본 개시사항의 화합물은 일반식 2의 화합물 또는 이의 이성질체, 약학적으로 허용가능한 염, 용매화물, 결정, 등배전자체 또는 전구약물이다.Additionally, in some specific embodiments, a compound of the present disclosure is a compound of Formula 2 or an isomer, pharmaceutically acceptable salt, solvate, crystal, isosteron, or prodrug thereof.
한편, 본 발명은 상기의 JAK을 표적으로 하는 JAK/STATs 신호전달 억제제를 포함하는 비정상적 JAK/STATs 신호전달로 말미암아 발생하는 질환의 예방 또는 치료용 약학 조성물을 제공한다.Meanwhile, the present invention provides a pharmaceutical composition for preventing or treating diseases caused by abnormal JAK/STATs signaling, including the JAK/STATs signaling inhibitor targeting the above JAKs.
본 발명의 일 실시예에 의하면, 본 발명에 따른 화합물(상기의 화학식 1 및 2)이 JAK/STAT 활성을 효과적으로 억제함을 확인한 바, 본 발명에 따른 화합물은 비정상적 JAK/STATs 신호전달로 말미암아 발생하는 질환을 효과적으로 예방 및 치료할 수 있을 것으로 판단된다.According to one embodiment of the present invention, it was confirmed that the compound according to the present invention (Formula 1 and 2 above) effectively inhibits JAK/STAT activity, and the compound according to the present invention causes abnormal JAK/STATs signaling. It is believed that it can effectively prevent and treat diseases.
본 발명의 약학 조성물에 있어, 상기 비정상적 JAK/STATs 신호전달로 말미암아 발생하는 질환은, 바람직하게는 염증성 자가면역질환 또는 암이다.In the pharmaceutical composition of the present invention, the disease caused by abnormal JAK/STATs signaling is preferably an inflammatory autoimmune disease or cancer.
JAK3는 IL-2, IL-4, IL-5 및 IL-21 (이뿐 아니라 다른 사이토카인)의 신호전달에 사용될 수 있다. 따라서 JAK3 유전자에 돌연변이가 있는 환자는 종종 면역 체계의 여러 측면에 영향을 미치는 문제를 경험한다. 예를 들어, 기능이 없는 JAK3는 SCID를 유발하여 환자에게 NK 세포, B 세포 또는 T 세포가 없는 결과를 초래하며, 이는 SCID 개체를 감염에 취약하게 만든다. JAK3로 신호를 보낼 수 있는 STAT5 단백질의 돌연변이는 자가면역 질환을 일으키는 것으로 알려졌다.JAK3 can be used for signaling of IL-2, IL-4, IL-5, and IL-21 (as well as other cytokines). Therefore, patients with mutations in the JAK3 gene often experience problems that affect multiple aspects of the immune system. For example, non-functional JAK3 can cause SCID, resulting in patients lacking NK cells, B cells, or T cells, making SCID individuals vulnerable to infection. Mutations in the STAT5 protein, which can signal to JAK3, are known to cause autoimmune diseases.
STAT1 및 STAT2에 돌연변이가 있는 환자는 종종 박테리아 및 바이러스 감염이 발생할 가능성이 더 높다고 알려졌다. 또한, STAT4 돌연변이는 류마티스 관절염과 관련이 있으며, STAT6 돌연변이는 천식과 관련이 있다. 결함이 있는 JAK-STAT 신호 경로를 가진 환자는 또한 피부 질환을 경험할 수 있다. 예를 들어, 비기능성 사이토카인과 STAT3의 과발현은 둘 다 건선과 관련이 있다. STAT3는 IL-23 수용체의 생성을 제어할 수 있고 IL-23은 Th17 세포의 발달을 도울 수 있으며, Th17 세포는 건선을 유도할 수 있기 때문에 STAT3는 건선에서 중요한 역할을 한다. 또한, 많은 사이토카인이 STAT3 전사 인자를 통해 기능하기 때문에 STAT3는 피부 면역 유지에 중요한 역할을 한다. 또한, JAK3 유전자 돌연변이 환자는 기능적인 T 세포, B 세포, NK 세포가 없기 때문에 피부 감염이 발생할 가능성이 더 높다.It is known that patients with mutations in STAT1 and STAT2 are often more likely to develop bacterial and viral infections. Additionally, STAT4 mutations are associated with rheumatoid arthritis, and STAT6 mutations are associated with asthma. Patients with a defective JAK-STAT signaling pathway may also experience skin disorders. For example, overexpression of non-functional cytokines and STAT3 are both associated with psoriasis. STAT3 plays an important role in psoriasis because STAT3 can control the production of IL-23 receptors, IL-23 can help the development of Th17 cells, and Th17 cells can induce psoriasis. Additionally, because many cytokines function through the STAT3 transcription factor, STAT3 plays an important role in maintaining skin immunity. Additionally, patients with JAK3 gene mutations are more likely to develop skin infections because they lack functional T cells, B cells, and NK cells.
한편, JAK/STAT 신호는 세포 분열에 관여하는 유전자의 전사를 허용할 수 있으므로 과도한 JAK/STAT 신호의 잠재적인 영향 중 하나는 암의 형성이다. 높은 수준의 STAT 활성화는 암과 관련이 있다. 특히 많은 양의 STAT3 및 STAT5 활성화는 대부분 위험한 종양과 관련이 있다. 예를 들어 너무 많은 STAT3 활성은 치료 후 흑색종(피부암)이 재발할 가능성을 높이며, 비정상적으로 높은 수준의 STAT5 활성은 전립선암으로 인한 환자 사망 가능성을 더 높인다. 과도하게 활성화된 JAK/STAT 신호는 또한 유방암 발생에 관여할 수 있다. 유선의 JAK/STAT 신호는 임신과 사춘기 동안 세포분열을 촉진하고 세포사멸을 감소시킬 수 있으므로 과도하게 활성화되면 암이 형성될 수 있다. JAK2의 돌연변이는 백혈병과 림프종을 유발할 수 있다. 특히, JAK2 유전자의 엑손 12, 13, 14 및 15의 돌연변이는 림프종이나 백혈병 발병의 위험 인자로 알려졌다. 돌연변이 STAT3 및 STAT5는 NK 및 T 세포에서 JAK/STAT 신호를 증가시킬 수 있으며, 이는 이들 세포의 매우 높은 증식을 촉진하고 백혈병 발병 가능성을 증가시킨다. 또한, 백혈병 환자에서는 일반적으로 적혈구의 발달을 허용하는 에리스로포이에틴 (EPO)에 의해 매개되는 JAK/STAT 신호 전달 경로가 변경될 수 있다. 즉, 과도한 JAK/STAT 신호가 일부 암 및 면역 장애의 원인이 되는 것으로 점차 알려짐에 따라 JAK 억제제가 이들 질병에 대한 치료제로써 제안되고 있다. 일 예로 일부 형태의 백혈병을 치료하기 위하여 JAK를 표적으로 삼아 억제하면 EPO 신호의 영향을 억제하고 백혈병을 예방할 수 있다. On the other hand, JAK/STAT signaling can allow transcription of genes involved in cell division, so one of the potential effects of excessive JAK/STAT signaling is the formation of cancer. High levels of STAT activation are associated with cancer. In particular, high amounts of STAT3 and STAT5 activation are most often associated with dangerous tumors. For example, too much STAT3 activity makes melanoma (skin cancer) more likely to recur after treatment, and abnormally high levels of STAT5 activity make patients more likely to die from prostate cancer. Hyperactivated JAK/STAT signaling may also be involved in breast cancer development. JAK/STAT signaling in the mammary gland can promote cell division and reduce apoptosis during pregnancy and puberty, so excessive activation may lead to cancer formation. Mutations in JAK2 can cause leukemia and lymphoma. In particular, mutations in exons 12, 13, 14, and 15 of the JAK2 gene are known to be risk factors for developing lymphoma or leukemia. Mutant STAT3 and STAT5 can increase JAK/STAT signaling in NK and T cells, which promotes very high proliferation of these cells and increases the likelihood of developing leukemia. Additionally, the JAK/STAT signaling pathway mediated by erythropoietin (EPO), which normally allows the development of red blood cells, may be altered in leukemia patients. In other words, as it is increasingly known that excessive JAK/STAT signaling is the cause of some cancers and immune disorders, JAK inhibitors are being proposed as treatments for these diseases. For example, to treat some forms of leukemia, targeting and inhibiting JAK can inhibit the effects of EPO signaling and prevent leukemia.
또한, STAT3를 표적으로 하는 치료법은 암 환자의 생존율을 향상시킬 수 있다는 보고가 알려졌으며, STAT3를 표적으로 하는 또 다른 약물(Tofacitinib)은 건선, 류마티스 관절염의 치료에 사용되고 있으며, 크론병 및 궤양성 대장염 치료제로도 승인된 바 있다. In addition, it has been reported that treatment targeting STAT3 can improve the survival rate of cancer patients, and another drug targeting STAT3 (Tofacitinib) is used to treat psoriasis, rheumatoid arthritis, Crohn's disease, and ulcerative colitis. It has also been approved as a treatment for colitis.
본 발명에서, 염증성 자가면역질환은, 일 예로 류마티스 관절염, 루푸스, 다발성 경화증, 건선, 염증성 대장염, 궤양성 대장염, 크론병, 탈모, 쇼그렌 증후군, 베체트병, 강직성 척추염, 제1형 당뇨병, 백반증, 피부근염, 경피증, 섬유조직염, IgA 신염 중 선택되는 어느 하나일 수 있다.In the present invention, inflammatory autoimmune diseases include, for example, rheumatoid arthritis, lupus, multiple sclerosis, psoriasis, inflammatory colitis, ulcerative colitis, Crohn's disease, alopecia, Sjogren's syndrome, Behcet's disease, ankylosing spondylitis, type 1 diabetes, vitiligo, It may be any one selected from dermatomyositis, scleroderma, fibromyositis, and IgA nephritis.
또한 본 발명에서, 암은, 일 예로 고형암 및 혈액암을 포함하는 것일 수 있다. 이때, 상기 고형암은 일 예로 간암, 피부암, 폐암, 대장암, 위암, 유방암, 결장암, 골암, 췌장암, 뇌종양, 경부암, 자궁암, 난소암, 직장암, 식도암, 소장암, 항문부근암, 나팔관암종, 자궁내막암종, 자궁경부암종, 질암종, 음문암종, 전립선암, 방광암, 신장암, 수뇨관암, 신장세포암종, 신장골반암종 및 중추신경계 종양 중 선택되는 어느 하나일 수 있으나 이에 반드시 제한되는 것은 아니다. 상기 혈액암은 일 예로 백혈병, 림프종 및 다발골수증 중 선택되는 어느 하나일 수 있으나 이에 반드시 제한되지 않는다.Additionally, in the present invention, cancer may include, for example, solid cancer and blood cancer. At this time, the solid cancer is, for example, liver cancer, skin cancer, lung cancer, colon cancer, stomach cancer, breast cancer, colon cancer, bone cancer, pancreas cancer, brain tumor, cervical cancer, uterine cancer, ovarian cancer, rectal cancer, esophagus cancer, small intestine cancer, anal cancer, fallopian tube carcinoma, and uterus. It may be any one selected from endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, prostate cancer, bladder cancer, kidney cancer, ureteral cancer, renal cell carcinoma, renal pelvic carcinoma, and central nervous system tumor, but is not necessarily limited thereto. For example, the blood cancer may be any one selected from leukemia, lymphoma, and multiple myelosis, but is not necessarily limited thereto.
본 발명에서 사용되는 용어, "예방"이란 본 발명에 따른 약학적 조성물의 투여에 의해 비정상적 JAK/STATs 신호전달로 말미암아 발생하는 질환을 억제하거나 발병을 지연시키는 모든 행위를 의미한다.As used in the present invention, the term "prevention" refers to all actions that suppress or delay the onset of diseases caused by abnormal JAK/STATs signaling by administration of the pharmaceutical composition according to the present invention.
본 발명에서 사용되는 용어, "치료"란 본 발명에 따른 약학적 조성물의 투여에 의해 비정상적 JAK/STATs 신호전달로 말미암아 발생하는 질환에 의한 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미한다.As used in the present invention, the term "treatment" refers to any action in which the symptoms of a disease caused by abnormal JAK/STATs signaling are improved or beneficially changed by administration of the pharmaceutical composition according to the present invention.
본 발명의 상기 화합물 (JAK을 표적으로 하는 JAK/STATs 신호전달 억제제)은 상기 성분에 추가로 동일 또는 유사한 기능을 나타내는 유효성분을 1종 이상 함유할 수 있다.The compound of the present invention (JAK/STATs signaling inhibitor targeting JAK) may contain one or more active ingredients that exhibit the same or similar functions in addition to the above ingredients.
본 발명의 약학적 조성물은 본 발명에 따른 화합물 (JAK을 표적으로 하는 JAK/STATs 신호전달 억제제) 이외에 약학적으로 허용 가능한 담체를 추가로 포함할 수 있다.The pharmaceutical composition of the present invention may further include a pharmaceutically acceptable carrier in addition to the compound according to the present invention (JAK/STATs signaling inhibitor targeting JAK).
본 발명에서 사용될 수 있는 담체의 종류는 특별히 제한되지 아니하며, 당해 기술 분야에서 통상적으로 사용되는 담체라면 어느 것이든 사용할 수 있다. 상기 담체의 비제한적인 예로는, 락토오스, 덱스트로오스, 수크로오스, 솔비톨, 만니톨, 식염수, 멸균수, 링거액, 완충 식염수, 알부민 주사 용액, 자일리톨, 에리스리톨, 말티톨, 말토덱스트린, 글리세롤, 에탄올 등을 들 수 있다. 이들은 단독으로 사용되거나 2종 이상을 혼합하여 사용될 수 있다.The type of carrier that can be used in the present invention is not particularly limited, and any carrier commonly used in the art can be used. Non-limiting examples of the carrier include lactose, dextrose, sucrose, sorbitol, mannitol, saline solution, sterile water, Ringer's solution, buffered saline solution, albumin injection solution, xylitol, erythritol, maltitol, maltodextrin, glycerol, ethanol, etc. You can. These may be used alone or in combination of two or more types.
또한, 본 발명의 약학적 조성물은 필요한 경우, 항산화제, 부형제, 희석제, 완충액 또는 정균제 등 기타 약학적으로 허용 가능한 첨가제들을 첨가하여 사용할 수 있으며, 계면 활성제, 결합제, 충진제, 증량제, 습윤제, 붕해제, 분산제 또는 윤활제 등을 부가적으로 첨가하여 사용할 수 있다.In addition, the pharmaceutical composition of the present invention can be used by adding other pharmaceutically acceptable additives, such as antioxidants, excipients, diluents, buffers or bacteriostatic agents, if necessary, as well as surfactants, binders, fillers, extenders, wetting agents, and disintegrants. , it can be used by additionally adding a dispersant or lubricant.
본 발명의 약학적 조성물에 있어서, 본 발명에 따른 화합물 (JAK을 표적으로 하는 JAK/STATs 신호전달 억제제)는 약학적 조성물의 전체의 중량을 기준으로 0.00001중량％ 내지 99.99중량％로 포함될 수 있으며, 바람직하게는 0.1중량% 내지 90중량%, 보다 바람직하게는 0.1중량% 내지 70중량%, 더욱 바람직하게는 0.1중량% 내지 50중량%로 포함될 수 있으나, 이에 한정되지 않으며 투여 대상의 상태, 구체적인 병증의 종류, 진행 정도 등에 따라 다양하게 변경될 수 있다. 필요한 경우, 약학적 조성물의 전체 함량으로도 포함될 수 있다.In the pharmaceutical composition of the present invention, the compound according to the present invention (JAK/STATs signaling inhibitor targeting JAK) may be included in an amount of 0.00001% to 99.99% by weight based on the total weight of the pharmaceutical composition. Preferably, it may be included in an amount of 0.1% by weight to 90% by weight, more preferably in 0.1% by weight to 70% by weight, and even more preferably in an amount of 0.1% by weight to 50% by weight, but is not limited thereto and may vary depending on the condition of the administration subject and specific symptoms. It can change in various ways depending on the type, degree of progress, etc. If necessary, it may also be included in the total content of the pharmaceutical composition.
즉, 본 발명의 약학적 조성물의 약학적 유효량, 유효 투여량은 약학적 조성물의 제제화 방법, 투여 방식, 투여 시간 및/또는 투여 경로 등에 의해 다양해질 수 있으며, 약학적 조성물의 투여로 달성하고자 하는 반응의 종류와 정도, 투여 대상이 되는 개체의 종류, 연령, 체중, 일반적인 건강 상태, 질병의 증세나 정도, 성별, 식이, 배설, 해당 개체에 동시 또는 이시에 함께 사용되는 약물 기타 조성물의 성분 등을 비롯한 여러 인자 및 의약 분야에서 잘 알려진 유사 인자에 따라 다양해질 수 있으며, 당해 기술 분야에서 통상의 지식을 가진 자는 목적하는 치료에 효과적인 투여량을 용이하게 결정하고 처방할 수 있다. 예를 들어, 본 발명의 약학적 조성물의 일일 투여량은 약 0.01 내지 1,000mg/kg이고, 바람직하게는 0.1 내지 100mg/kg이며, 하루 일회 내지 수회에 나누어 투여할 수 있다.That is, the pharmaceutically effective amount and effective dosage of the pharmaceutical composition of the present invention may vary depending on the formulation method, administration method, administration time, and/or administration route of the pharmaceutical composition, and the desired effect to be achieved by administration of the pharmaceutical composition Type and degree of reaction, type of subject to be administered, age, weight, general health condition, symptoms or severity of disease, gender, diet, excretion, drugs used simultaneously or simultaneously with the subject, other composition components, etc. It may vary depending on various factors including and similar factors well known in the pharmaceutical field, and a person skilled in the art can easily determine and prescribe an effective dosage for the desired treatment. For example, the daily dosage of the pharmaceutical composition of the present invention is about 0.01 to 1,000 mg/kg, preferably 0.1 to 100 mg/kg, and can be administered once or in divided doses several times a day.
본 발명의 약학적 조성물의 투여는 하루에 1회 투여될 수 있고, 수 회에 나누어 투여될 수도 있다. 본 발명의 약학적 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있다. 상기 요소를 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양으로 투여할 수 있으며, 이는 당업자에 의해 용이하게 결정될 수 있다.The pharmaceutical composition of the present invention may be administered once a day, or may be administered in several divided doses. The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents. Considering all of the above factors, it can be administered in an amount that can achieve maximum effect with the minimum amount without side effects, and this can be easily determined by a person skilled in the art.
본 발명의 약학적 조성물은 상기한 질환을 예방 또는 치료하기 위하여 추가적으로 호르몬 치료, 약물치료 등의 다양한 방법들과 병용하여 사용될 수 있다.The pharmaceutical composition of the present invention can be used in combination with various methods such as hormone therapy and drug therapy to prevent or treat the above diseases.
본 발명에서 사용된 용어, "투여"는 어떠한 적절한 방법으로 환자에게 본 발명의 약학적 조성물을 도입하는 것을 의미하며, 본 발명의 약학적 조성물의 투여 경로 및 투여 방식은 각각 독립적일 수 있으며, 목적하는 해당 부위에 상기 약학적 조성물이 도달할 수 있는 한, 특별한 제한 없이 임의의 투여 경로 및 투여 방식에 따를 수 있다.The term "administration" used in the present invention means introducing the pharmaceutical composition of the present invention into a patient by any appropriate method, and the administration route and mode of administration of the pharmaceutical composition of the present invention may be independent, respectively. As long as the pharmaceutical composition can reach the relevant area, it can be administered by any route and method of administration without particular limitations.
상기 약학적 조성물은 경구 투여 또는 비경구 투여 방식으로 투여할 수 있으며, 경구 투여 또는 비경구 투여를 위한 적합하고 다양한 제형으로 제제화되어 사용될 수 있다.The pharmaceutical composition can be administered by oral or parenteral administration, and can be formulated and used in various dosage forms suitable for oral or parenteral administration.
본 발명의 약학적 조성물을 이용한 경구 투여용 제제의 비제한적인 예로는, 유성 현탁액, 트로키제(troches), 로젠지(lozenge), 정제, 수용성 현탁액, 조제 분말, 과립, 에멀젼, 하드 캡슐, 소프트 캡슐, 시럽 또는 엘릭시르제 등을 들 수 있다.Non-limiting examples of preparations for oral administration using the pharmaceutical composition of the present invention include oily suspensions, troches, lozenges, tablets, aqueous suspensions, preparation powders, granules, emulsions, hard capsules, and soft capsules. Capsules, syrups, or elixirs may be used.
본 발명의 약학적 조성물을 경구 투여용으로 제제화하기 위하여, 솔비톨, 만니톨, 전분, 아밀로펙틴, 셀룰로오스 락토오스, 사카로오스 또는 젤라틴 등과 같은 결합제; 스테아르산 마그네슘, 스테아르산 칼슘, 스테아릴 푸마르산 나트륨 또는 폴리에틸렌 글리콜 왁스 등과 같은 윤활유; 디칼슘 포스페이트 등과 같은 부형제; 옥수수 전분 또는 고구마 전분 등과 같은 붕해제 등을 사용할 수 있으며, 방향제, 시럽제, 감미제 등도 사용할 수 있다. 나아가 캡슐제의 경우에는 상기 언급한 물질 외에도 지방유와 같은 액체 담체 등을 추가로 사용할 수 있다.In order to formulate the pharmaceutical composition of the present invention for oral administration, binders such as sorbitol, mannitol, starch, amylopectin, cellulose lactose, saccharose or gelatin; lubricants such as magnesium stearate, calcium stearate, sodium stearyl fumarate, or polyethylene glycol wax; excipients such as dicalcium phosphate; Disintegrants such as corn starch or sweet potato starch can be used, and fragrances, syrups, sweeteners, etc. can also be used. Furthermore, in the case of capsules, in addition to the above-mentioned substances, a liquid carrier such as fatty oil can be additionally used.
본 발명의 약학적 조성물의 비경구 투여 방법으로는, 근육 내 투여, 경피 투여, 정맥 내 투여, 복강 내 투여 또는 피하 투여 등을 이용할 수 있으며, 상기 조성물을 질환 부위에 도포하거나 분무, 흡입하는 방법 또한 이용할 수 있으나 이에 제한되지 않는다.Parenteral administration methods of the pharmaceutical composition of the present invention include intramuscular administration, transdermal administration, intravenous administration, intraperitoneal administration, or subcutaneous administration. Methods include applying the composition to the diseased area, spraying it, or inhaling it. It can also be used, but is not limited to this.
본 발명의 약학적 조성물을 이용한 비경구용 제제의 비제한적인 예로는, 주사액, 좌제, 연고, 도포용 파우더, 오일, 호흡기 흡입용 분말, 스프레이용 에어로졸제, 크림 등을 들 수 있다.Non-limiting examples of parenteral preparations using the pharmaceutical composition of the present invention include injection solutions, suppositories, ointments, powders for application, oils, powders for respiratory inhalation, aerosol preparations for sprays, creams, etc.
본 발명의 약학적 조성물을 비경구 투여용으로 제제화하기 위하여, 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결 건조 제제, 외용제 등을 사용할 수 있으며, 상기 비수성용제, 현탁제로는 올리브 오일과 같은 식물성 기름, 프로필렌글리콜, 폴리에틸렌글리콜, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다.To prepare the pharmaceutical composition of the present invention for parenteral administration, sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, topical preparations, etc. can be used, and the non-aqueous solvents and suspensions include olive oil, etc. Injectable esters such as vegetable oil, propylene glycol, polyethylene glycol, and ethyl oleate can be used.
본 발명의 약학적 조성물을 주사액으로 제제화하는 경우, 본 발명의 약학적 조성물을 안정제 또는 완충제와 함께 물에서 혼합하여 용액 또는 현탁액으로 제조하고 이를 앰플(ampoule) 또는 바이알(vial)의 단위 투여용으로 제제화할 수 있다.When the pharmaceutical composition of the present invention is formulated as an injection solution, the pharmaceutical composition of the present invention is mixed in water with a stabilizer or buffer to prepare a solution or suspension, which is then administered in ampoules or vials for unit administration. It can be formulated.
본 발명의 약학적 조성물을 에어로졸제로 제제화하는 경우, 수분산된 농축물 또는 습윤 분말이 분산되도록 추진제 등이 첨가제와 함께 배합할 수 있다.When the pharmaceutical composition of the present invention is formulated as an aerosol, a propellant or the like can be mixed with additives to disperse the water-dispersed concentrate or wet powder.
본 발명의 약학적 조성물을 연고, 오일, 크림, 도포용 파우더, 피부 외용제 등으로 제제화하는 경우에는, 동물성 유, 식물성 유, 왁스, 파라핀, 폴리에틸렌 글리콜, 실리콘, 벤토나이트, 실리카, 탈크, 전분, 트라칸트, 셀룰로오스 유도체, 산화 아연 등을 담체로 사용하여 제제화할 수 있다.When the pharmaceutical composition of the present invention is formulated into ointments, oils, creams, powders for application, external skin preparations, etc., animal oil, vegetable oil, wax, paraffin, polyethylene glycol, silicone, bentonite, silica, talc, starch, trimethylamine, etc. It can be formulated using Kant, cellulose derivatives, zinc oxide, etc. as carriers.
한편, 본 발명은 상기의 JAK을 표적으로 하는 JAK/STATs 신호전달 억제제를 포함하는 비정상적 JAK/STATs 신호전달로 말미암아 발생하는 질환의 개선용 식품 조성물을 제공한다.Meanwhile, the present invention provides a food composition for improving diseases caused by abnormal JAK/STATs signaling, including the JAK/STATs signaling inhibitor targeting the above JAK.
본 발명의 일 실시예에 의하면, 본 발명에 따른 화합물 (상기의 화학식 1 및 2)이 JAK/STAT 활성을 효과적으로 억제함을 확인한바, 본 발명에 따른 화합물은 비정상적 JAK/STATs 신호전달로 말미암아 발생하는 질환을 효과적으로 개선할 수 있을 것으로 판단된다.According to one embodiment of the present invention, it was confirmed that the compound according to the present invention (Formula 1 and 2 above) effectively inhibits JAK/STAT activity, and the compound according to the present invention causes abnormal JAK/STATs signaling. It is believed that it can effectively improve the disease.
본 발명의 식품 조성물에 있어, 상기 화합물 (JAK을 표적으로 하는 JAK/STATs 신호전달 억제제)의 함량은 특별히 제한되지 않으며, 투여 대상의 상태, 구체적인 병증의 종류, 진행 정도 등에 따라 다양하게 변경될 수 있다. 필요한 경우, 식품의 전체 함량으로도 포함될 수 있다.In the food composition of the present invention, the content of the compound (JAK/STATs signaling inhibitor targeting JAK) is not particularly limited and may vary depending on the condition of the administration subject, the type of specific disease, the degree of progression, etc. there is. If necessary, it can also be included in the total amount of the food.
본 발명의 식품 조성물은 일 예로, 면류, 껌류, 유제품류, 아이스크림류, 육류, 곡류, 카페인 음료, 일반음료, 초콜릿, 빵류, 스낵류, 과자류, 사탕, 피자, 젤리, 알코올성 음료, 술, 비타민 복합제 및 그 밖의 건강보조식품류 중 선택되는 어느 하나일 수 있으나, 반드시 이에 한정되는 것은 아니다.Food compositions of the present invention include, for example, noodles, gums, dairy products, ice cream, meat, grains, caffeinated beverages, general beverages, chocolate, bread, snacks, confectionery, candy, pizza, jelly, alcoholic beverages, alcohol, and vitamin complexes. and other health supplements, but is not necessarily limited thereto.
본 발명의 식품 조성물이 식품 첨가물의 형태로 사용될 경우, 이를 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다.When the food composition of the present invention is used in the form of a food additive, it can be added as is or used together with other foods or food ingredients, and can be used appropriately according to conventional methods.
또한, 본 발명의 "식품 조성물"은 건강기능식품을 포함하는 의미를 포괄하는데, 상기 "건강기능식품"이라 함은 건강기능식품에 관한 법률 제6727호에 따른 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및 가공한 식품을 의미하며, "기능성"이라 함은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건 용도에 유용한 효과를 얻을 목적으로 섭취하는 것을 의미한다.In addition, “food composition” of the present invention encompasses health functional foods, and the term “health functional foods” refers to raw materials or ingredients that have functionality useful to the human body according to Act No. 6727 on Health Functional Foods. It refers to food manufactured and processed using , and “functional” means ingestion for the purpose of controlling nutrients for the structure and function of the human body or obtaining useful effects for health purposes such as physiological effects.
이하, 본 발명의 내용을 하기 실시예 또는 실험예를 통해 더욱 상세히 설명하고자 한다. 다만, 본 발명의 권리범위가 하기 실시예 또는 실험예에만 한정되는 것은 아니고, 그와 등가의 기술적 사상의 변형까지를 포함한다.Hereinafter, the contents of the present invention will be described in more detail through the following examples or experimental examples. However, the scope of the present invention is not limited to the following examples or experimental examples, and includes modifications of the technical idea equivalent thereto.
[[ 실시예Example 1: One: JAKJAK // STATsSTATs 신호전달 억제제(MDR 화합물)의 발굴] Discovery of signal transduction inhibitors (MDR compounds)]
JAK을 표적으로 하는 JAK/STATs 신호전달 억제제를 발굴하기 위하여, 한국화합물은행에서 화합물 라이브러리를 분양받아 사용하였으며, 스크리닝에 의하여 선정된 활성화합물의 골격구조를 포함하는 라이브러리로부터 최적화 과정을 진행하여 후보물질을 발굴하였다.In order to discover JAK/STATs signaling inhibitors targeting JAK, a compound library was purchased and used from the Korea Chemical Bank, and an optimization process was performed from the library containing the skeletal structure of the active compound selected through screening to identify candidate substances. was discovered.
그 결과, 발굴된 2종류의 후보물질은 하기 화학식 3 (MDR-2201) 및 하기 화학식 4 (MDR-2202)의 구조를 갖는 것으로 확인되었다. MDR-2201 및 MDR-2202는 각각 하기 화학식 1 및 화학식 2와 같이 중심골격으로 벤조-이미다조-피리딘(benzo-imidazo-pyridine)을 가지며, 피리딘 링(pyridine ring)에 -OH기(hydroxyl group) 또는 케톤기(ketone group(=O))를 가진 케토-엔올 호변 이성질체(keto-enol tautomerism) 구조이다. 발굴된 MDR-2201, MDR-2202는 각각 화학식 3 및 화학식 4에서 보듯이, 각각 화학식 1 및 화학식 2에서, R1이 페놀기, R2가 시아노기로 치환된 것이다.As a result, the two types of candidate substances discovered were confirmed to have the structures of Formula 3 (MDR-2201) and Formula 4 (MDR-2202). MDR-2201 and MDR-2202 have a central skeleton of benzo-imidazo-pyridine as shown in the following formulas (1) and (2), respectively, and a -OH group (hydroxyl group) in the pyridine ring. Or, it is a keto-enol tautomerism structure with a ketone group (=O). As shown in Chemical Formulas 3 and 4, the discovered MDR-2201 and MDR-2202, respectively, have R1 substituted with a phenol group and R2 substituted with a cyano group in Chemical Formulas 1 and 2, respectively.
[화학식 1][Formula 1]
[화학식 2][Formula 2]
[화학식 3][Formula 3]
[화학식 4][Formula 4]
[[ 실험예Experiment example 1: 발굴된 화합물의 1: Of the discovered compounds JAKJAK // STATsSTATs 신호전달 억제 효능 평가] [Evaluation of signal transduction inhibition efficacy]
1. 세포배양1. Cell culture
초파리 세포주인 S2-NP 세포는 10% FBS와 1% 페니실린/스트렙토마이신이 첨가된 SD 배지(Schneider's Drosophila Medium)에서 25℃가 유지되는 세포배양기에서 배양하였다. S2-NP 세포에 리포터(reporter) 시스템으로 10×STAT92E-루시퍼레이즈(Luciferase)가 안전하게 발현되도록 확립한 세포인 S2-NP/10×STAT92E-Luc 세포는 10% FBS, 1% 페니실린/스트렙토마이신과 500㎍/㎖의 제네티신(geneticin)이 첨가된 SD 배지에서 25℃가 유지되는 세포배양기에서 배양하였다.S2-NP cells, a Drosophila cell line, were cultured in SD medium (Schneider's Drosophila Medium) supplemented with 10% FBS and 1% penicillin/streptomycin in a cell incubator maintained at 25°C. S2-NP/10×STAT92E-Luc cells, which are cells established to safely express 10×STAT92E-Luciferase as a reporter system in S2-NP cells, were incubated with 10% FBS, 1% penicillin/streptomycin, and The cells were cultured in a cell culture medium maintained at 25°C in SD medium supplemented with 500 μg/ml geneticin.
인간 호지킨 림프종 세포주인 HDLM-2와 L540 세포는 20% FBS와 1% 페니실린/스트렙토마이신이 첨가된 RPMI 배지에서 5% CO2와 37℃가 유지되는 세포배양기에서 배양하였다.Human Hodgkin's lymphoma cell lines HDLM-2 and L540 cells were cultured in RPMI medium supplemented with 20% FBS and 1% penicillin/streptomycin in a cell culture medium maintained at 5% CO 2 and 37°C.
2. 2. STAT92ESTAT92E 활성 activation 억제능inhibitory ability 평가 evaluation
S2-NP 세포(2×106 cells/well)를 6-웰 플레이트에 분주하고 배양하였으며, 24시간 후 Effectene transfection reagent를 이용하여 Upd 플라스미드 (사이토카인의 일종인 Upd를 발현하는 플라스미드)를 형질도입(transient transfection)하였다. 형질도입 24시간 후 Upd 플라스미드가 형질도입된 S2-NP 세포(8×105 cells/㎖)와 S2-NP/10×STAT92E-Luc 세포(4×105 cells/㎖)를 혼합하여 96-웰 플레이트에 적당량 분주하고 각각의 화합물 시료와 함께 24시간 동안 배양하였다.S2-NP cells (2× 106 cells/well) were distributed and cultured in a 6-well plate, and after 24 hours, Upd plasmid (plasmid expressing Upd, a type of cytokine) was transduced using Effectene transfection reagent. (transient transfection) was performed. 24 hours after transduction, Upd plasmid-transduced S2-NP cells (8×10 5 cells/ml) and S2-NP/10×STAT92E-Luc cells (4×10 5 cells/ml) were mixed and cultured in 96-wells. An appropriate amount was dispensed onto the plate and incubated with each compound sample for 24 hours.
음성 대조군은 Upd(사이토카인의 일종)를 형질도입하지 않은 S2-NP 세포와 S2-NP/10×STAT92E-Luc 세포를 동일하게 분주하였으며, 화합물 시료 대신 동일한 농도의 DMSO를 처리하였다. 양성 대조군은 Upd를 도입한 S2-NP 세포와 S2-NP/10×STAT92E-Luc 세포를 동일하게 분주하였으며, 화합물 시료 대신 동일한 농도의 DMSO를 처리하였다. As a negative control, S2-NP cells and S2-NP/10×STAT92E-Luc cells that were not transduced with Upd (a type of cytokine) were distributed equally, and the same concentration of DMSO was treated instead of the compound sample. As a positive control, S2-NP cells and S2-NP/10×STAT92E-Luc cells introduced with Upd were distributed equally, and the same concentration of DMSO was treated instead of the compound sample .
각각의 시료에 대한 효능을 평가하기 위하여, 루미노미터(luminometer)를 이용하여 STAT92E 루시퍼레이즈 활성과 Renillar 루시퍼레이즈 활성을 측정하였으며, STAT92E 루시퍼레이즈 활성/Renilla 루시퍼레이즈 활성의 비례값으로 산출하였다. 모든 시료의 루시퍼레이즈 값은 음성대조군을 1로 하여 상대적인 값(relative luciferase units, RLUs)으로 표기였다.To evaluate the efficacy of each sample, STAT92E luciferase activity and Renilla luciferase activity were measured using a luminometer, and calculated as the proportional value of STAT92E luciferase activity/Renilla luciferase activity. The luciferase values of all samples were expressed as relative luciferase units (RLUs), with the negative control being set as 1.
실험 결과, MDR-2201 (화학식 3)과 MDR-2202 (화학식 4)를 여러 농도로 초파리 세포에 처리하였을 때 두 화합물은 STAT92E 루시퍼레이즈 활성을 농도의존적으로 억제하였으며, 두 화합물의 IC50은 1.0 μM 이하로 확인되었다(도 1 및 표 1). 도 1은 본 발명에 따른 화합물의 STAT92E 활성 억제능을 평가한 결과이다.As a result of the experiment, when MDR-2201 (Formula 3) and MDR-2202 (Formula 4) were treated with Drosophila cells at various concentrations, the two compounds inhibited STAT92E luciferase activity in a concentration-dependent manner, and the IC 50 of both compounds was 1.0 μM. The following was confirmed (Figure 1 and Table 1). Figure 1 shows the results of evaluating the ability of compounds according to the present invention to inhibit STAT92E activity.
3. 3. JAKJAK /STAT 인산화 /STAT phosphorylation 억제능inhibitory ability 평가 evaluation
JAK 표적에 의한 JAK/STAT 신호전달 억제능을 평가하기 위하여, JAK 패밀리 단백질 (JAK1, JAK2, JAK3, TYK2) 및 하위 신호인 STAT3 활성에 대한, 화합물 MDR-2201 및 MDR-2202의 효능을 HDLM-2와 L540 세포에서 평가하였다. HDLM-2 세포는 JAK1/JAK2/TYK2/STATs 경로가, L540 세포는 JAK3/STATs 경로가 특이적으로 활성화된 세포이다.To evaluate the ability to inhibit JAK/STAT signaling by JAK targets, the efficacy of compounds MDR-2201 and MDR-2202 on the activity of JAK family proteins (JAK1, JAK2, JAK3, TYK2) and downstream signal STAT3 was measured in HDLM-2. and L540 cells. HDLM-2 cells are cells in which the JAK1/JAK2/TYK2/STATs pathway is specifically activated, and L540 cells are cells in which the JAK3/STATs pathway is specifically activated.
HDLM-2와 L540 세포를 각각의 화합물과 함께 24시간 동안 배양하였으며, 4종의 JAK 패밀리와 STAT3 인산화에 대한 효능을 평가하고자, 세포를 용해 버퍼(lysis buffer)로 용해하고 단백질을 정량하였으며, 일정량의 단백질을 SDS-PAGE에서 전기영동하여 단백질을 분리하여 PVDF 멤브레인에 이동하고 5% 탈지유에서 블록킹한 후 1차 항체로 반응하였다. 이후, 멤브레인을 TBS-T에서 30분간 3회 세척하고 2차 항체로 반응하였으며, ECL로 반응시켜 암실에서 단백질 발현을 확인하였다.HDLM-2 and L540 cells were cultured with each compound for 24 hours. To evaluate the efficacy on phosphorylation of the four JAK families and STAT3, cells were lysed with lysis buffer and proteins were quantified. The proteins were separated by electrophoresis on SDS-PAGE, transferred to a PVDF membrane, blocked in 5% skim milk, and reacted with primary antibodies. Afterwards, the membrane was washed three times for 30 minutes in TBS-T, reacted with secondary antibody, and reacted with ECL to confirm protein expression in the dark.
실험 결과, 화합물 MDR-2201 (화학식 3)과 MDR-2202 (화학식 4)를 각각 10 μM 처리하고 24시간 동안 배양하였을 때, 각각의 화합물은 4종의 JAK 패밀리 및 STAT3 단백질의 인산화를 효과적으로 억제하여 JAK/STAT 신호전달을 억제함을 확인할 수 있었다. (도 2). 도 2는 본 발명에 따른 화합물의 JAK/STAT 활성 억제능을 평가한 결과이다.As a result of the experiment, when compounds MDR-2201 (Formula 3) and MDR-2202 (Formula 4) were treated with 10 μM each and cultured for 24 hours, each compound effectively inhibited the phosphorylation of four types of JAK family and STAT3 proteins. It was confirmed that JAK/STAT signaling was inhibited. (Figure 2). Figure 2 shows the results of evaluating the JAK/STAT activity inhibition ability of the compound according to the present invention.
HDLM-2 세포는 JAK1/JAK2/TYK2/STATs 경로가, L540 세포는 JAK3/STATs 경로가 특이적으로 활성화된 세포된 세포이기 때문에, 도 2에서 HDLM-2 세포는 pY-JAK3의 웨스턴블롯 결과가 대조군 및 실험군 모두에서 안 나오고, L540 세포는 pY-JAK1, pY-JAK2 및 pY-TYK2의 웨스턴블록 결과가 대조군 및 실험군 모두에서 안 나오게 되는 것이다.Since HDLM-2 cells are cells in which the JAK1/JAK2/TYK2/STATs pathway is specifically activated, and L540 cells are cells in which the JAK3/STATs pathway is specifically activated, the Western blot results of pY-JAK3 for HDLM-2 cells in Figure 2 are It does not appear in both the control and experimental groups, and for L540 cells, the Western block results of pY-JAK1, pY-JAK2, and pY-TYK2 do not appear in both the control and experimental groups.
[[ 실험예Experiment example 2: 발굴된 화합물과 2: Discovered compounds and JAKJAK 패밀리family 단백질 사이의 결합 구조 분석] Analysis of bond structure between proteins]
1. 실험 개요1. Experiment overview
표적 단백질인 4개의 JAK 패밀리 단백질에 대한 서열 유사성(sequence similarity)과 결합 부위 유사성(binding site similarity)을 분석하였으며, 이를 바탕으로 본 발명에서 발굴한 화합물과 JAK 키나아제 부위에서의 상호작용 부위(interaction site)에 대한 연관성을 분석하였다. 또한, 화합물의 삼차원적 구조와 QM(quantum mechanics)를 계산하여 물질의 안정성을 예측하였다. JAK 패밀리 단백질의 효소활성 도메인(kinase domain)에 대한 화합물의 단백질 도킹(molecular docking)에 의한 결합 모드(binding mode)는 Discovery Studio Program을 이용하여 분석하였다. 각각의 JAK 단백질에 대한 PDB ID는 6HZU(JAK1), 2B7A(JAK2), 4HVD(JAK3) 및 4GIH(TYK2)를 사용하였다.We analyzed the sequence similarity and binding site similarity for the four JAK family proteins, which are target proteins. Based on this, we analyzed the interaction site between the compound discovered in the present invention and the JAK kinase site. ) was analyzed for correlation. In addition, the stability of the material was predicted by calculating the three-dimensional structure and QM (quantum mechanics) of the compound. The binding mode of the compound to the enzyme domain (kinase domain) of the JAK family protein was analyzed using the Discovery Studio Program. The PDB IDs for each JAK protein were 6HZU (JAK1), 2B7A (JAK2), 4HVD (JAK3), and 4GIH (TYK2).
2. 단백질 결합 부위의 분석2. Analysis of protein binding sites
JAK 패밀리 단백질의 JAK 동질효소(isozymes)에 대한 MDR 화합물의 단백질 결합 부위 분석을 위하여, MDR 화합물의 3D 구조 예측 및 결합 모드를 예측하였다. 서열 유사성(sequence similarity), 결합 부위 유사성(binding site similarity) 및 단백질 결합 부위(protein binding site)를 종합적으로 분석한 결과, 각 JAK 표적 단백질에서 결합 모드는 4개의 JAK 동질효소(isozyme)에 대해 유사할 것으로 예측되었다 (도 3 및 표 2). 도 3은 본 발명에 따른 화합물의 JAK 동질효소(isozyme)의 키나아제(kinase) 부위 서열 유사성 및 결합 부위 유사성을 확인한 결과이다.To analyze the protein binding site of the MDR compound to the JAK isozymes of the JAK family proteins, the 3D structure and binding mode of the MDR compound were predicted. As a result of comprehensive analysis of sequence similarity, binding site similarity, and protein binding site, the binding mode for each JAK target protein was similar for the four JAK isozymes. It was predicted that (Figure 3 and Table 2). Figure 3 shows the results of confirming the sequence similarity and binding site similarity of the JAK isozyme of the compound according to the present invention.
또한, 하기 표 3에 나타낸 바와 같이, QM 분석에서 호변 이성질체(tautomer)인 이미다조-피리딘(imidazo-pyridine) 부분을 스캐폴드(scaffold)로 지정하여 입체형태(conformation)을 예측하였을 때, MDR-2201 (화학식 3)과 MDR-2202 (화학식 4)는 각각 -343,546.94 및 -343,557.90kcal/mol로 MDR-2202가 단백질-화합물 결합에서 더욱 안정한 구조로 예측되었다.In addition, as shown in Table 3 below, when the conformation was predicted by designating the imidazo-pyridine portion, which is a tautomer, as a scaffold in QM analysis, MDR- 2201 (Formula 3) and MDR-2202 (Formula 4) were -343,546.94 and -343,557.90 kcal/mol, respectively, and MDR-2202 was predicted to be a more stable structure in protein-compound binding.
3. 본 발명 MDR 화합물의 3. MDR compound of the present invention JAKJAK kinasekinase domain에 대한 about domain 결합능Binding capacity 분석 analyze
MDR 화합물의 JAK 키나아제 도메인(kinase domain)에 대한 결합능을 화합물 모델링(molecular modeling)으로 평가하여 결합에너지를 예측하였다.The binding ability of the MDR compound to the JAK kinase domain was evaluated using molecular modeling to predict the binding energy.
분석을 위하여 각 JAK 표적 단백질의 키나아제 도메인에 대한 X-ray crystal structure를 이용하여 결합 포켓(binding pocket) 내에서 이미다조-피리딘(imidazo-pyridine)의 방향을 Discovery Studio Program을 이용하여 분석하였다.For analysis, the direction of imidazo-pyridine within the binding pocket was analyzed using the Discovery Studio Program using the X-ray crystal structure of the kinase domain of each JAK target protein.
실험 결과, 결합모드 예측에서, MDR-2201 (화학식 3)과 MDR-2202 (화학식 4)는 각각의 JAK 단백질에 효과적으로 결합하여 인산화효소의 활성을 저해하였으며, MDR-2021 화합물은 JAK1 > JAK3 ≥ TYK2 > JAK2의 순으로, MDR-2022 화합물은 TYK2 > JAK1 > JAK3 > JAK2의 순으로 강하게 결합하는 것으로 확인되었다.As a result of the experiment, in predicting the binding mode, MDR-2201 (Formula 3) and MDR-2202 (Formula 4) effectively bound to each JAK protein and inhibited the activity of the kinase, and the MDR-2021 compound was JAK1 > JAK3 ≥ TYK2 > In the order of JAK2, the MDR-2022 compound was confirmed to bind strongly in the order of TYK2 > JAK1 > JAK3 > JAK2.
특히, MDR-2202 (화학식 4)의 결합 에너지가 MDR-2201 (화학식 3)보다 안정적이며, MDR-2202 (화학식 4)에서 힌지 영역 수소결합 상호작용이 강할 것으로 예측된다.In particular, the binding energy of MDR-2202 (Formula 4) is more stable than that of MDR-2201 (Formula 3), and the hinge region hydrogen bond interaction is predicted to be strong in MDR-2202 (Formula 4).
또한, 단백질 결합 부위의 포켓(binding pocket) 내의 소수성(hydrophobicity) 및 친수성(hydrophilicity)이 모두 강하여 MDR 화합물의 친수성 및 소수성 잔기가 동시에 존재하여 결합 포켓(binding pocket)으로 점유하는 것이 안정한 것으로 예측된다.In addition, both hydrophobicity and hydrophilicity within the binding pocket of the protein binding site are strong, so it is predicted that the hydrophilic and hydrophobic residues of the MDR compound exist simultaneously and are stable when occupying the binding pocket.
이에, 화학식 3 및 4의 중심골격인 화학식 1 및 화학식 2의 R1 위치에는 -CH3, -C(CH3)3, -(CH2)n-CH3 (n은 1-5), 페닐기(phenyl group), 이소프로필기(isopropyl group), 사이클로헥실기(cyclohexyl group), 사이클로펜탄기(cyclopentane group), 사이클로펜타디엔기(cyclopentadiene group), 메틸사이클로펜타디엔기(methyl cyclopentadiene group) 등과 같은 소수성 그룹이 위치할 수 있으며, R2 위치에는 시아노기(cyano group)가 위치할 수 있다 (도 4 및 표 4). Accordingly, at the R1 position of Formulas 1 and 2, which are the central skeleton of Formulas 3 and 4, -CH 3 , -C(CH 3 ) 3 , -(CH 2 )n-CH 3 (n is 1-5), phenyl group ( Hydrophobic groups such as phenyl group, isopropyl group, cyclohexyl group, cyclopentane group, cyclopentadiene group, methyl cyclopentadiene group, etc. A group may be located, and a cyano group may be located at the R2 position (Figure 4 and Table 4).
도 4는 본 발명에 따른 화합물의 JAK 동질효소(isozyme)의 키나아제(kinase) 단백질 결합 부위를 분석한 결과이다.Figure 4 shows the results of analysis of the kinase protein binding site of the JAK isozyme of the compound according to the present invention.
(kcal/(kcal/
molmol
))
Claims (9)
[화학식 1]
[화학식 2]
상기 화학식 1 및 화학식 2의 R1은 -CH3, -C(CH3)3, -(CH2)n-CH3 (n은 1-5), 페닐기(phenyl group), 이소프로필기(isopropyl group), 사이클로헥실기(cyclohexyl group), 사이클로펜탄기(cyclopentane group), 사이클로펜타디엔기(cyclopentadiene group), 메틸사이클로펜타디엔기(methyl cyclopentadiene group) 중 선택되는 어느 하나이며,
상기 화학식 1 및 화학식 2의 R2는 시아노기(cyano group)인, JAK을 표적으로 하는 JAK/STATs 신호전달 억제제.
Contains a compound having the structure of Formula 1 or Formula 2 below as an active ingredient,
[Formula 1]
[Formula 2]
R1 in Formulas 1 and 2 is -CH 3 , -C(CH 3 ) 3 , -(CH 2 )n-CH 3 (n is 1-5), a phenyl group, and an isopropyl group. ), a cyclohexyl group, a cyclopentane group, a cyclopentadiene group, or a methyl cyclopentadiene group,
A JAK/STATs signaling inhibitor targeting JAK, wherein R2 in Formulas 1 and 2 is a cyano group.
상기 비정상적 JAK/STATs 신호전달로 말미암아 발생하는 질환은, 염증성 자가면역질환 또는 암인, 약학 조성물.
A pharmaceutical composition for preventing or treating diseases caused by abnormal JAK/STATs signaling comprising the JAK/STATs signaling inhibitor targeting JAK according to claim 1,
The disease caused by the abnormal JAK/STATs signaling is an inflammatory autoimmune disease or cancer. Pharmaceutical composition.
상기 염증성 자가면역질환은,
류마티스 관절염, 루푸스, 다발성 경화증, 건선, 염증성 대장염, 궤양성 대장염, 크론병, 탈모, 쇼그렌 증후군, 베체트병, 강직성 척추염, 제1형 당뇨병, 백반증, 피부근염, 경피증, 섬유조직염, IgA 신염 중 선택되는 어느 하나인, 약학 조성물.
According to paragraph 2,
The inflammatory autoimmune disease is,
Choose from rheumatoid arthritis, lupus, multiple sclerosis, psoriasis, inflammatory colitis, ulcerative colitis, Crohn's disease, alopecia, Sjögren's syndrome, Behçet's disease, ankylosing spondylitis, type 1 diabetes, vitiligo, dermatomyositis, scleroderma, fibromyositis, and IgA nephritis. Any one of which is a pharmaceutical composition.
상기 암은,
고형암 및 혈액암을 포함하는 것인, 약학 조성물.
According to paragraph 2,
The cancer is
A pharmaceutical composition comprising solid cancer and hematological cancer.
상기 비정상적 JAK/STATs 신호전달로 말미암아 발생하는 질환은, 염증성 자가면역질환 또는 암인, 식품 조성물.
A food composition for improving diseases caused by abnormal JAK/STATs signaling comprising the JAK/STATs signaling inhibitor targeting JAK according to claim 1,
A food composition wherein the disease caused by abnormal JAK/STATs signaling is an inflammatory autoimmune disease or cancer.
상기 염증성 자가면역질환은, 류마티스 관절염, 루푸스, 다발성 경화증, 건선, 염증성 대장염, 궤양성 대장염, 크론병, 탈모, 쇼그렌 증후군, 베체트병, 강직성 척추염, 제1형 당뇨병, 백반증, 피부근염, 경피증, 섬유조직염, IgA 신염중 선택되는 어느 하나인, 식품 조성물.
According to clause 6,
The inflammatory autoimmune diseases include rheumatoid arthritis, lupus, multiple sclerosis, psoriasis, inflammatory colitis, ulcerative colitis, Crohn's disease, alopecia, Sjogren's syndrome, Behcet's disease, ankylosing spondylitis, type 1 diabetes, vitiligo, dermatomyositis, scleroderma, A food composition selected from fibrositis and IgA nephritis.
상기 암은,
고형암 및 혈액암을 포함하는 것인, 식품 조성물.According to clause 6,
The cancer is
A food composition comprising solid cancer and hematological cancer.
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| KR102396717B1 (en) | 2014-04-08 | 2022-05-11 | 인사이트 코포레이션 | Treatment of b-cell malignancies by a combination jak and pi3k inhibitor |
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| KR102225840B1 (en) | 2016-07-14 | 2021-03-11 | 일라이 릴리 앤드 캄파니 | Pyrazolylaminobenzimidazole derivatives as JAK inhibitors |
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