WO2022068075A1 - 化合物zju-37在制备肝脏疾病预防和/或治疗药物中的应用 - Google Patents

化合物zju-37在制备肝脏疾病预防和/或治疗药物中的应用 Download PDF

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WO2022068075A1
WO2022068075A1 PCT/CN2020/136273 CN2020136273W WO2022068075A1 WO 2022068075 A1 WO2022068075 A1 WO 2022068075A1 CN 2020136273 W CN2020136273 W CN 2020136273W WO 2022068075 A1 WO2022068075 A1 WO 2022068075A1
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zju
compound
liver
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陈智
楼国华
刘艳宁
李爱春
葛田田
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Zhejiang University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

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  • the invention relates to the field of medicine, and specifically discloses the application of compound ZJU-37 in the preparation of medicaments for the prevention and/or treatment of liver diseases.
  • Acute and chronic liver injury is a common clinical disease. If it is not controlled and treated in time, it will develop into irreversible diseases such as severe hepatitis and liver failure. The fatality rate of acute liver failure is as high as 80% to 97%. %. At present, there is still no effective clinical treatment and drugs for severe hepatitis and liver failure. Therefore, it is urgent to develop new therapeutic drugs and develop new treatment methods and methods to improve the survival rate of severe hepatitis. Studies have shown that receptor-interacting protein kinase RIP1 is involved in various liver diseases. The use of RIP1 protein kinase inhibitors can reduce cell death and alleviate various inflammatory responses, but the specific mechanism is unclear.
  • RIP1 kinase inhibition is mainly aimed at neurodegenerative diseases and autoimmune diseases, including ulcerative colitis, psoriasis, rheumatoid arthritis and so on.
  • RIP1-involved cell death can promote tissue inflammation and damage, if not inhibit or even amplify tissue damage. Therefore, the development of targeting RIP1 kinase activity has clinical needs and broad application prospects.
  • the purpose of the present invention is to overcome the defects of the prior art and provide a new use of the compound ZJU-37.
  • the liver disease is liver injury, hepatitis, liver failure, liver tissue necrosis/apoptosis.
  • the liver injury may be acute liver injury.
  • the hepatitis may be severe hepatitis.
  • the liver failure may be acute liver failure.
  • the second aspect of the present invention provides new uses of the compound ZJU-37 of formula I, including the use of any one or more of the following medicaments.
  • the present invention discovers for the first time the application of compound ZJU-37 in the preparation of medicaments for the treatment of liver diseases, and opens up the application field of compound ZJU-37.
  • the present invention provides a new treatment mode and a treatment drug for serious liver diseases such as severe hepatitis and liver failure, and has obvious liver protection and treatment effects and obvious social benefits.
  • Figure 1 shows the comparison of the therapeutic effects of compound ZJU-37 and Nec-1s on liver injury and systemic inflammation in a mouse model of acute liver failure
  • Figure A and Figure B show the comparison of serum liver injury indexes ALT and AST levels in the LPS/GalN model group
  • the normal control group was significantly increased, and the serum ALT and AST levels in the treatment group were significantly decreased.
  • Compound ZJU-37 could significantly improve ALT and AST compared with commercial Nec-1s. Serum ALT and AST were reduced after Nec-1s treatment (LPS/GalN vs. Nec-1s: 1053 ⁇ 107.7 vs. 724.8 ⁇ 119.5). And ZJU-37 can significantly reduce ALT (LPS/GalN vs.
  • Figure 2 shows the comparison of compound ZJU-37 and Nec-1s on liver pathological improvement and neutrophil infiltration in a mouse model of acute liver failure
  • Figures A and B represent the LPS/GalN model group
  • HE staining of liver tissue shows the liver Tissue necrosis and inflammatory cell infiltration were evident.
  • the compound ZJU-37 treatment group and the Nec-1s treatment group had significantly reduced liver tissue necrosis and inflammatory cell infiltration ( Figures C, D). Histopathological sections showed little necrosis of liver tissue and less inflammatory cell infiltration.
  • the immunohistochemistry of hepatic neutrophils by using Ly6G was consistent with HE staining.
  • FIG 3 shows the comparison of compound ZJU-37 and Nec-1s on liver cell death in a mouse model of acute liver failure; TUNEL-positive cells in the LPS/D-GalN model group were significantly increased compared with the normal control group (Panels A, B), while There was almost no TUNEL positive signal in the normal control group, indicating that a large number of liver cells underwent apoptosis in the model group.
  • the expression of TUNEL was significantly down-regulated in the treatment group; especially the compound ZJU-37 had the best effect, and histopathological sections of mouse liver tissue showed that the TUNEL signal was almost undetectable in liver tissue ( Figures C, D).
  • the compound ZJU-37 of the present invention belongs to the prior art, and can be prepared by the existing method.
  • Animal models are research tools to verify the effectiveness of new therapeutic drugs and new treatments.
  • the animal models used internationally to simulate liver failure include drug-induced liver failure models (acetaminophen model, LPS/GalN model, sulfur acetamide model, carbon tetrachloride model, etc.), acute hepatic ischemia model, partial hepatectomy model, etc.
  • the LPS/GalN model is an ideal animal model of liver failure because of its good reproducibility, no obvious extrahepatic toxicity, and the liver injury performance is close to clinical.
  • mice Six-week-old male C57BL/6 mice (purchased from Nanjing Institute of Biomedicine) were randomly divided into normal control group, model group (LPS/GalN group), and compound ZJU-37 treatment group (5 mg/kg ZJU-37+LPS/ GalN group), compound Nec-1s treatment group (5mg/kg Nec-1s+LPS/GalN group).
  • Compound ZJU-37 and Nec-1s were injected intraperitoneally, and 30 minutes later, LPS/GalN (40 ⁇ g/kg LPS+800 mg/kg D-GalN) was injected intraperitoneally to make a model; the model group was replaced by an equal volume of solvent in compound ZJU-37 ; The normal control group was not treated.
  • the LPS/GalN model was established for 6 hours, and the blood was collected by removing the eyeball for biochemical and CBA detection.
  • Figure A and Figure B show that the levels of serum liver injury indexes ALT and AST in the LPS/GalN model group were significantly higher than those in the normal control group, and the serum ALT and AST levels in the treatment group were significantly lower.
  • Compound ZJU ⁇ 37 Compared with commercial Nec-1s, it can significantly improve ALT, AST. Serum ALT and AST were reduced after Nec-1s treatment (LPS/GalN vs. Nec-1s: 1053 ⁇ 107.7 vs. 724.8 ⁇ 119.5). And ZJU-37 can significantly reduce ALT (LPS/GalN vs.
  • compound ZJU-37 can better reduce liver injury and improve systemic inflammation in LPS/GalN-induced acute liver failure in mice at the same dose.
  • mice Six-week-old male C57BL/6 mice (purchased from Nanjing Institute of Biomedicine) were randomly divided into normal control group, model group (LPS/GalN group), and compound ZJU-37 treatment group (5 mg/kg ZJU-37+LPS/ GalN group), compound Nec-1s treatment group (5mg/kg Nec-1s+LPS/GalN group).
  • Compound ZJU-37 and Nec-1s were injected intraperitoneally, and 30 minutes later, LPS/GalN (40 ⁇ g/kg LPS+800 mg/kg D-GalN) was injected intraperitoneally to make a model; the model group was replaced by an equal volume of solvent in compound ZJU-37 ; The normal control group was not treated.
  • LPS/GalN modeling liver samples were collected for HE and immunohistochemical staining.
  • Figures A and B represent the LPS/GalN model group.
  • HE staining of liver tissue showed that liver tissue necrosis and inflammatory cell infiltration were obvious.
  • the compound ZJU-37 treatment group and the Nec-1s treatment group had significantly reduced liver tissue necrosis and inflammatory cell infiltration ( Figures C, D). Histopathological sections showed little necrosis of liver tissue and less inflammatory cell infiltration.
  • the immunohistochemistry of hepatic neutrophils by using Ly6G was consistent with HE staining.
  • compound ZJU-37 can better improve the liver pathology and reduce the infiltration of neutrophils in LPS/GalN-induced acute liver failure in mice under the same dose.
  • Example 4 Compound ZJU-37 inhibits apoptosis of liver tissue in LPS/GalN model mice
  • mice Six-week-old male C57BL/6 mice (purchased from Nanjing Institute of Biomedicine) were randomly divided into normal control group, model group (LPS/GalN group), and compound ZJU-37 treatment group (5 mg/kg ZJU-37+LPS/ GalN group), compound Nec-1s treatment group (5mg/kg Nec-1s+LPS/GalN group).
  • Compound ZJU-37 and Nec-1s were injected intraperitoneally, and 30 minutes later, LPS/GalN (40 ⁇ g/kg LPS+800 mg/kg D-GalN) was injected intraperitoneally to make a model; the model group was replaced by an equal volume of solvent in compound ZJU-37 ; The normal control group was not treated. After 6 hours of LPS/GalN modeling, liver tissue was collected for TUNEL staining.
  • TUNEL-positive cells in the LPS/D-GalN model group were significantly increased compared with the normal control group ( Figures A, B), while the normal control group had almost no TUNEL-positive signal, indicating that a large number of liver cells were apoptosis in the model group. Death.
  • the expression of TUNEL was significantly down-regulated in the treatment group; especially the compound ZJU-37 had the best effect, and histopathological sections of mouse liver tissue showed that the TUNEL signal was almost undetectable in liver tissue ( Figures C, D).
  • compound ZJU-37 can better improve liver cell death in LPS/GalN-induced acute liver failure in mice. This may also be a potential mechanism for the difference in the efficacy of the two drugs.

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Abstract

涉及医药领域，具体公开了式I化合物ZJU-37在制备肝脏疾病预防和/或治疗药物中的应用。经过广泛而深入的研究，发现了化合物ZJU-37在制备肝脏疾病治疗药物中的用途，开拓了化合物ZJU-37的应用领域。同时，为重症肝炎、肝衰竭等重大肝脏疾病提供了治疗方式与治疗药物，其肝脏保护和治疗作用明显，具有明显的社会效益。

Description

化合物ZJU-37在制备肝脏疾病预防和/或治疗药物中的应用 技术领域
本发明涉及医药领域，具体公开了化合物ZJU-37在制备肝脏疾病预防和/或治疗药物中的应用。
背景技术
急、慢性肝损伤是目前临床上的一种常见疾病，如未得到及时的控制和治疗，将会发展为重症肝炎、肝衰竭等不可逆性疾病，其中急性肝衰竭的病死率高达80％～97％。目前，对于重症肝炎、肝衰竭临床上尚缺乏有效的治疗手段及药物。因此亟待研发新的治疗药物，开拓新的治疗手段和方法，以提升重症肝炎的救治存活率。研究表明，受体相互作用蛋白激酶RIP1参与各种肝脏疾病。使用RIP1蛋白激酶抑制剂可以减少细胞的死亡和减轻各种炎症反应，但具体机制不清楚。目前处在临床阶段的RIP1激酶抑制主要针对的是神经退行性疾病和自身免疫性疾病，包括溃疡性肠炎，银屑病，类风湿关节炎等。RIP1参与的细胞死亡可以促进组织炎症和损伤，如果不抑制甚至放大组织的损伤，因此靶向RIP1激酶活性的研发具有临床的需求和广阔的应用前景。
发明内容
本发明的目的是克服现有技术的缺陷，提供化合物ZJU-37的新用途。
本发明的第一方面，提供式I化合物ZJU-37在制备肝脏疾病预防和/或治疗药物中的应用。
Figure PCTCN2020136273-appb-000001
优选地，所述肝脏疾病为肝损伤、肝炎、肝衰竭、肝组织坏死/凋亡。
其中，所述肝损伤可以是急性肝损伤。所述肝炎可以是重症肝炎。所述肝衰竭可以是急性肝衰竭。
本发明的第二方面，提供式I化合物ZJU-37的新用途，包括制备以下药物的中的任一 项或多项的用途。
Figure PCTCN2020136273-appb-000002
(1)能够降低ALT水平的药物
(2)能够降低AST水平的药物
(3)能够减轻肝损伤程度的药物
(4)能够缓解肝脏炎症的药物
(5)能够降低肝组织坏死程度的药物
(6)降低炎细胞浸润的药物
(7)抑制炎症因子分泌的药物
(8)抑制肝组织的凋亡和程序性坏死的药物。
与现有技术相比，本发明的有益效果为：
本发明经过广泛而深入的研究，首次发现了化合物ZJU-37在制备肝脏疾病治疗药物中的用途，开拓了化合物ZJU-37的应用领域。同时，本发明为重症肝炎、肝衰竭等重大肝脏疾病提供了新的治疗方式与治疗药物，其肝脏保护和治疗作用明显，具有明显的社会效益。
附图说明
图1显示化合物ZJU‐37与Nec‐1s在小鼠急性肝衰竭模型中对肝脏损伤和全身炎症的疗效比较；图A，图B表示LPS/GalN模型组血清肝脏损伤指标ALT、AST水平均较正常对照组显著升高，治疗组血清ALT、AST水平均显著降低，化合物ZJU‐37较之商品化Nec‐1s更能显著改善ALT,AST。Nec‐1s治疗后可以减少血清ALT，AST(LPS/GalN vs.Nec‐1s:1053±107.7vs.724.8±119.5)。而ZJU‐37可以显著的减少ALT(LPS/GalN vs.ZJU‐37:2110±307.2vs.166±31.11)和AST(LPS/GalN vs.ZJU‐37:21053±107.7vs.206.5±21.16)(图A，B)。我们使用CBA检测各组血清细胞因子水平。结果显示相比Nec‐1s,化合物ZJU‐37可以更好的减少TNFα,IL‐6,IFN‐γ,MCP‐1的产生(图C‐F)。同时ZJU‐37相比于Nec‐1s可以延长小鼠生存时间(图G)。于LPS/GalN造模前30分钟进行同等剂量(5mg/kg)的化合物ZJU‐37或商品化Nec‐1s腹腔给药，化合物ZJU‐37较之商品化Nec‐1s更能显著改善肝脏损伤和全身炎症。
图2显示了化合物ZJU‐37与Nec‐1s在小鼠急性肝衰竭模型中对肝脏病理改善和中性粒细胞浸润的比较；图A,B表示LPS/GalN模型组，肝组织HE染色显示肝脏组织坏死及炎细胞浸润明显。化合物ZJU-37治疗组和Nec-1s治疗组较之模型组，其肝组织坏死程度和炎细胞浸润均显著降低(图C,D)；尤以化合物ZJU-37的疗效最佳，小鼠肝组织病理切片显示肝组织几无坏死，炎细胞浸润也更少。通过使用Ly6G对肝脏中性粒细胞进行免疫组织化学，结果与HE染色一致，化合物ZJU-37治疗组和Nec-1s治疗组较之模型组，其肝组织中性粒浸润均显著降低；尤以化合物ZJU-37的疗效明显，小鼠肝组织病理切片显示肝组织几无中性粒细胞浸润(图E-H)。比例尺50uM。
图3显示化合物ZJU‐37与Nec‐1s在小鼠急性肝衰竭模型中对肝脏细胞死亡的比较；LPS/D-GalN模型组TUNEL阳性细胞较正常对照组显著增加(图A,B)，而正常对照组几乎无TUNEL阳性信号，说明大量肝脏细胞在模型组发生凋亡。治疗组中TUNEL的表达显著下调；尤以化合物ZJU-37的疗效最佳，小鼠肝组织病理切片显示肝组织几乎检测不到TUNEL信号(图C,D)。
具体实施方式
在进一步描述本发明具体实施方式之前，应理解，本发明的保护范围不局限于下述特定的具体实施方案；还应当理解，本发明实施例中使用的术语是为了描述特定的具体实施方案，而不是为了限制本发明的保护范围。
除非另外定义，本发明中使用的所有技术和科学术语与本技术领域技术人员通常理解的意义相同。除实施例中使用的具体方法、设备、材料外，根据本技术领域的技术人员对现有技术的掌握及本发明的记载，还可以使用与本发明实施例中所述的方法、设备、材料相似或等同的现有技术的任何方法、设备和材料来实现本发明。
本发明所述化合物ZJU-37为现有技术，可通过现有方法制备获得。
实施例1化合物ZJU-37溶液的配制
实验方法：化合物ZJU-37，采用DMSO助溶后配制成的化合物ZJU-37的储存液，于注射前以PBS稀释配成化合物ZJU-37的溶剂。
实施例2化合物ZJU-37和Nec-1s对LPS/GalN诱导的小鼠急性肝衰竭肝损伤和全身炎症的研究
实验方法：
动物模型是验证新的治疗药物、新的治疗手段是否有效的研究工具，目前国际上采用的 模拟肝衰竭的动物模型有药物性肝衰竭模型(对-乙酰氨基酚模型、LPS/GalN模型、硫代乙酰胺模型、四氯化碳模型等)、急性肝缺血模型、部分肝切除模型等。其中LPS/GalN模型，因其可重复性好，肝外毒性不明显，肝损伤表现接近临床等优势，是一种较为理想的肝衰竭动物模型。
六周龄雄性C57BL/6小鼠(购于南京生物医药研究院)随机分为正常对照组、模型组(LPS/GalN组)、化合物ZJU-37治疗组(5mg/kg ZJU-37+LPS/GalN组)、化合物Nec-1s治疗组(5mg/kg Nec-1s+LPS/GalN组)。化合物ZJU-37和Nec-1s进行腹腔注射，30分钟后LPS/GalN(40μg/kg LPS+800mg/kg D-GalN)腹腔注射造模；模型组以等体积的溶剂代替化合物ZJU-37的溶剂；正常对照组不做处理。LPS/GalN造模6小时摘眼球法取血进行生化和CBA检测。
实验结果：
实验结果如图1所示：图A，图B表示LPS/GalN模型组血清肝脏损伤指标ALT、AST水平均较正常对照组显著升高，治疗组血清ALT、AST水平均显著降低，化合物ZJU‐37较之商品化Nec‐1s更能显著改善ALT,AST。Nec‐1s治疗后可以减少血清ALT，AST(LPS/GalN vs.Nec‐1s:1053±107.7vs.724.8±119.5)。而ZJU‐37可以显著的减少ALT(LPS/GalN vs.ZJU‐37:2110±307.2vs.166±31.11)和AST(LPS/GalN vs.ZJU‐37:21053±107.7vs.206.5±21.16)(图A，B)。我们使用CBA检测各组血清细胞因子水平。结果显示相比Nec‐1s,化合物ZJU‐37可以更好的减少TNFα,IL‐6,IFN‐γ,MCP‐1的产生(图C‐F)。同时ZJU‐37相比于Nec‐1s可以延长小鼠生存时间(图G)。于LPS/GalN造模前30分钟进行同等剂量(5mg/kg)的化合物ZJU‐37或商品化Nec‐1s腹腔给药，化合物ZJU‐37较之商品化Nec‐1s更能显著改善肝脏损伤和全身炎症。
即，与Nec‐1s相比，同等剂量条件下化合物ZJU‐37可以更好地减少LPS/GalN诱导的小鼠急性肝衰竭的肝损伤和改善全身炎症。
实施例3化合物ZJU-37和Nec-1s对LPS/GalN诱导的小鼠急性肝衰竭肝脏病理和中性粒细胞浸润的研究
实验方法：
六周龄雄性C57BL/6小鼠(购于南京生物医药研究院)随机分为正常对照组、模型组(LPS/GalN组)、化合物ZJU-37治疗组(5mg/kg ZJU-37+LPS/GalN组)、化合物Nec-1s治疗组(5mg/kg Nec-1s+LPS/GalN组)。化合物ZJU-37和Nec-1s进行腹腔注射，30分钟后LPS/GalN(40μg/kg LPS+800mg/kg D-GalN)腹腔注射造模；模型组以等体积的溶剂代 替化合物ZJU-37的溶剂；正常对照组不做处理。LPS/GalN造模6小时后留取肝脏标本进行HE和免疫组织化学染色。
实验结果：
实验结果如图2所示：图A,B表示LPS/GalN模型组，肝组织HE染色显示肝脏组织坏死及炎细胞浸润明显。化合物ZJU-37治疗组和Nec-1s治疗组较之模型组，其肝组织坏死程度和炎细胞浸润均显著降低(图C,D)；尤以化合物ZJU-37的疗效最佳，小鼠肝组织病理切片显示肝组织几无坏死，炎细胞浸润也更少。通过使用Ly6G对肝脏中性粒细胞进行免疫组织化学，结果与HE染色一致，化合物ZJU-37治疗组和Nec-1s治疗组较之模型组，其肝组织中性粒浸润均显著降低；尤以化合物ZJU-37的疗效明显，小鼠肝组织病理切片显示肝组织几无中性粒细胞浸润(图E-H)。比例尺50uM。
即，同等剂量条件下化合物ZJU-37可以更好的改善LPS/GalN诱导的小鼠急性肝衰竭的肝脏病理并减少中性粒细胞的浸润。
实施例4化合物ZJU-37抑制LPS/GalN模型小鼠肝组织的凋亡
实验方法：
六周龄雄性C57BL/6小鼠(购于南京生物医药研究院)随机分为正常对照组、模型组(LPS/GalN组)、化合物ZJU-37治疗组(5mg/kg ZJU-37+LPS/GalN组)、化合物Nec-1s治疗组(5mg/kg Nec-1s+LPS/GalN组)。化合物ZJU-37和Nec-1s进行腹腔注射，30分钟后LPS/GalN(40μg/kg LPS+800mg/kg D-GalN)腹腔注射造模；模型组以等体积的溶剂代替化合物ZJU-37的溶剂；正常对照组不做处理。LPS/GalN造模6小时后留取肝脏组织进行TUNEL染色。
实验结果：
实验结果如图3所示：LPS/D-GalN模型组TUNEL阳性细胞较正常对照组显著增加(图A,B)，而正常对照组几乎无TUNEL阳性信号，说明大量肝脏细胞在模型组发生凋亡。治疗组中TUNEL的表达显著下调；尤以化合物ZJU-37的疗效最佳，小鼠肝组织病理切片显示肝组织几乎检测不到TUNEL信号(图C,D)。
即，化合物ZJU-37可以更好的改善LPS/GalN诱导的小鼠急性肝衰竭的肝脏细胞死亡。这也可能是两种药物药效差异的潜在机制。
以上的实施例是为了说明本发明公开的实施方案，并不能理解为对本发明的限制。此外，本文所列出的各种修改以及发明中方法、组合物的变化，在不脱离本发明的范围和精神的前提下对本领域内的技术人员来说是显而易见的。虽然已结合本发明的多种具体优选实施例对 本发明进行了具体的描述，但应当理解，本发明不应仅限于这些具体实施例。事实上，各种如上所述的对本领域内的技术人员来说显而易见的修改来获取发明都应包括在本发明的范围内。

Claims (10)

  1. 式I化合物ZJU-37在制备肝脏疾病预防和/或治疗药物中的应用
    Figure PCTCN2020136273-appb-100001
  2. 根据权利要求1所述的应用，其特征在于：所述肝脏疾病为肝损伤、肝炎、肝衰竭，或肝组织坏死/凋亡。
  3. 化合物ZJU-37在制备降低ALT水平的药物中的应用。
  4. 化合物ZJU-37在制备降低AST水平的药物中的应用。
  5. 化合物ZJU-37在制备减轻肝损伤程度的药物中的应用。
  6. 化合物ZJU-37在制备缓解肝脏炎症的药物中的应用。
  7. 化合物ZJU-37在制备降低肝组织坏死程度的药物中的应用。
  8. 化合物ZJU-37在制备降低炎细胞浸润的药物中的应用。
  9. 化合物ZJU-37在制备抑制炎症因子分泌的药物中的应用。
  10. 化合物ZJU-37在制备抑制肝组织的凋亡和程序性坏死的药物中的应用。
PCT/CN2020/136273 2020-09-30 2020-12-14 化合物zju-37在制备肝脏疾病预防和/或治疗药物中的应用 Ceased WO2022068075A1 (zh)

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