Combinations of SSAO inhibitors and GLP-1 receptor agonists and uses thereof

Abstract

The present invention relates to a combination of an SSAO inhibitor and a GLP-1 receptor agonist and uses thereof. Specifically, the present invention provides a pharmaceutical combination of an SSAO inhibitor and a GLP-1 receptor agonist, and uses thereof in the treatment of metabolism-related diseases, especially in the treatment of non-alcoholic fatty liver disease (NAFLD). The pharmaceutical composition can exhibit an effect that is improved compared to the use of an SSAO inhibitor and a GLP-1 receptor agonist (GLP-1RA) alone.

Description

Technical Field

[0001] This invention relates to the field of medicine, and specifically, it provides a strategy for treating liver diseases, particularly non-alcoholic steatohepatitis, by combining SSAO inhibitors with GLP-1 receptor agonists. Background Technology

[0002] Semicarbazide-sensitive amine oxidase (SSAO) is a dopaquinone-containing amine oxidase, belonging to the semicarbazide-sensitive amine oxidase family, and is also known as vascular adhesion protein 1 (VAP-1). In animals, it is primarily encoded by the AOC3 gene. SSAO is abundant in mammalian smooth muscle cells, adipocytes, and endothelial cells, and is also expressed in various organs such as the vascular system, cartilage, and kidneys. In mammals, SSAO exists in two types: membrane-bound and soluble. Enzyme activity varies greatly among different species and even among different tissues of the same species. SSAO catalyzes the metabolism of endogenous or dietary amines into aldehydes, producing hydrogen peroxide and ammonia in the process. Its natural metabolic substrates in vivo are mainly aliphatic and aromatic amines, among which methylamine (MA) and aminoacetone are recognized as physiological substrates of SSAO, catalyzing their conversion into formaldehyde and acetone aldehyde, respectively. In endothelial cells, SSAO exists in the form of vascular adhesion protein-1, which mediates the adhesion and exudation of leukocytes to endothelial cells.

[0003] Numerous studies have confirmed that SSAO and its metabolites are closely associated with atherosclerosis, diabetes and its complications, obesity, stroke, chronic kidney disease, retinopathy, chronic obstructive pulmonary disease (COPD), autoimmune diseases, multiple sclerosis, rheumatoid arthritis, arthritis-related pain, Alzheimer's disease, and other inflammatory diseases. SSAO / VAP-1 has been reported to play an important role in cancer biology; small molecule inhibitors of SSAO / VAP-1 reduce the number of pro-angiogenic bone marrow cells in melanoma and lymphoma. Recent studies have also suggested that SSAO dysfunction plays a role in the development and progression of liver diseases such as fatty liver disease.

[0004] Glucagon-like peptide-1 (GLP-1) is produced in the intestine and stimulates insulin secretion in a glucose-dependent manner while inhibiting glucagon secretion, reducing appetite and energy intake, and delaying gastric emptying. This class of drugs has also been shown to promote weight loss and lower systolic blood pressure (SBP), which may be beneficial for patients with type 2 diabetes. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) were launched as a new treatment in 2005 for the clinical treatment of type 2 diabetes (T2DM). In addition, GLP-1 receptor agonists have shown various therapeutic potentials in a variety of diseases such as obesity and metabolic disorders.

[0005] Fatty liver disease complicated by inflammation can progress to non-alcoholic fatty liver disease (NAFLD), and a certain percentage of patients will further progress to liver fibrosis, cirrhosis, and even liver cancer after a period of time. NAFLD is a series of liver abnormalities ranging from non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH), characterized by ectopic accumulation of lipids in the liver, progressive lobular inflammation, hepatocyte degeneration, and fibrosis. Its course is variable but can lead to cirrhosis, liver cancer, and other liver-related diseases. The pathogenesis of NASH is complex and not fully understood. It results from the simultaneous action of multiple factors, including genetic and epigenetic factors, dietary factors, mitochondrial dysfunction (oxidative stress), inflammatory responses, endoplasmic reticulum stress, and hypoxia. The oral thyroid hormone receptor (THR)-β selective agonist Resmetirom (MGL-3196) has been approved by the FDA for the treatment of NASH. Lifestyle modifications through diet and exercise, including weight loss, are currently the most important treatment measures for the prevention and treatment of NAFLD and its comorbidities.

[0006] Given the multiple biological functions of VAP-1, numerous studies have suggested that VAP-1 is a highly promising therapeutic target for NASH. Serum VAP-1 / SSAO levels and SSAO activity are correlated with the severity of NAFLD and its progression, particularly with the degree of liver fibrosis. In normal livers, VAP-1 expression is limited to vascular endothelial cells and hepatic sinusoids. In NASH livers, abnormally elevated VAP-1 expression is observed in the diaphragm. VAP-1's cell adhesion function plays an important role in the infiltration of immune cells, and its amine oxidase-mediated oxidative stress is closely related to the occurrence and progression of NASH, especially fibrosis. In cirrhotic livers, functional AOC3 expression has also been observed in α-SMA and CD90-positive interstitial cells. In vitro and in vivo experiments also suggest that VAP-1 can directly act on hepatic stellate cells to regulate fibrosis (Weston, 2015). VAP-1 can also regulate the rapid activation of NF-κB in endothelial cells, thereby inducing the expression of pro-inflammatory cytokines and adhesion proteins such as IL-8, CXCL8, E-selectin, and ICAM-1, thus regulating inflammation (Weston, 2015). In various liver fibrosis or NASH models, knocking out the Aoc3 gene or using VAP-1 inhibitors can alleviate symptoms of inflammation and liver fibrosis. In a NASH model using Aoc3 gene knock-in mice with inactivated amine oxidase, improved levels of inflammation and fibrosis in the liver were also observed, suggesting the important role of VAP-1-mediated amine oxidase activity in NASH (Weston, 2015; Stolen, 2005).

[0007] The liver contains GLP-1 receptors, and GLP-1 may exert its effects directly in the liver through these receptors. Both clinical and animal studies suggest that decreased GLP-1 levels and impaired GLP-1 receptor signaling pathways are closely related to the development and progression of NAFLD, providing a theoretical basis for the use of GLP-1 receptor agonists in the treatment of NAFLD.

[0008] The development of GLP-1 receptor agonists was primarily aimed at controlling glycemic homeostasis in the treatment of type 2 diabetes. However, later studies revealed that these drugs have multiple biological effects, including improving appetite, controlling body weight, lowering blood pressure, improving cardiac function, and affecting the central nervous system. GLP-1 receptor agonists can also indirectly improve NAFLD, with pathophysiological manifestations in two aspects: directly and indirectly improving insulin sensitivity by suppressing appetite and reducing body weight; GLP-1 receptor agonists can reduce appetite by acting on GLP-1 receptors in the hypothalamus, thereby reducing body weight. Insulin resistance in white adipose tissue is a major mechanism in the development of NAFLD. Currently, evidence from animal and clinical trials suggests that GLP-1 receptor agonist treatment can improve NAFLD, reduce hepatic fat content, and reduce inflammatory infiltration. The mechanisms are related to activating hepatic GLP-1 receptors, improving insulin resistance, reducing oxidative stress, attenuating endoplasmic reticulum stress, and regulating genes related to fatty acid synthesis and oxidation, which may prevent and delay the onset and progression of NAFLD.

[0009] Given the complexity of NASH pathogenesis, involving multiple pathological mechanisms such as metabolism, insulin resistance, inflammation, and liver fibrosis, single-drug therapy often offers limited benefits to patients. Simultaneously addressing metabolic issues, inflammation, hepatocellular damage, and liver fibrosis comprehensively presents a significant clinical challenge. Furthermore, some potential NASH treatments may pose safety risks or side effects, such as elevated blood lipids, itching, and pancreatitis. To better meet clinical needs and achieve better treatment outcomes for NASH, developing combination therapies that simultaneously regulate and treat multiple aspects of the disease has significant clinical application value. Summary of the Invention

[0010] This invention provides a combination of an SSAO inhibitor and a GLP-1 receptor agonist, and relates to the pharmaceutical composition and its uses. The proposed combination can more comprehensively regulate different aspects of the NASH pathogenesis, taking into account metabolism, inflammation, and fibrosis, producing a synergistic effect and providing a better treatment option and clinical benefits. The combined medication involves simultaneous, sequential, or alternating administration of the active drugs, resulting in an unexpected synergistic effect between the two drugs, thus achieving a better therapeutic effect than using either drug alone at the same dose. SSAO is a key inflammatory regulator; inhibiting SSAO is expected to comprehensively improve metabolism, suppress inflammation, provide multi-organ protection, and potentially prevent β-cell damage.

[0011] A first aspect of the present invention provides a pharmaceutical combination comprising:

[0012] (A) A therapeutically effective dose of an SSAO inhibitor; and

[0013] (B) Therapeutic effective dose of GLP-1 receptor agonist (GLP-1RA).

[0014] In another preferred embodiment, the SSAO inhibitor is selected from the group consisting of: small molecule SSAO inhibitors or pharmaceutically acceptable salts thereof, monoclonal antibodies or peptides.

[0015] In another preferred embodiment, the SSAO small molecule inhibitor has the structure shown in Formulas I and II, or its stereoisomers or racemates:

[0016]

[0017] R has a structure selected from the group consisting of: H, F, Cl, Br, -NO2, -OH, -CN, =O, or -(L1). m -R8; The L1 is selected from the following group: CH2, S(O), S(O)2, NHC(O), C(O), NH, O or S;

[0018] B is selected from the group consisting of: substituted or unsubstituted C3-12 cycloalkyl groups (including monocyclic, fused, bridged, and spirocyclic groups), substituted or unsubstituted C6-C10 aromatic rings (including monocyclic and fused rings), substituted or unsubstituted 5-12 membered heteroaromatic rings (including monocyclic and fused rings), and substituted or unsubstituted 3-12 membered heterocycles (including monocyclic, fused, bridged, and spirocyclic groups); wherein the heteroaromatic ring or heterocycle further contains 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur;

[0019] X is O or a chemical bond;

[0020] R1 is selected from the following group: H, halogens;

[0021] R2 is selected from the following group: H, halogens;

[0022] R3 is selected from the following group: H, -NH2, C1-C4 alkyl;

[0023] m is selected from the following group: 0, 1, 2, 3 or 4;

[0024] R8 is selected from the following group: H, C1-C4 alkyl, C1-C4 alkoxy, -(CH2). n -C3-C8 cycloalkyl, C6-C10 aryl, 5-10 heteroaryl, -(CH2) n -3-10 heterocyclic group, -NR a R b -NHR c ;R cSelected from the group consisting of: -C(=O)-(C1-C4 alkyl), -C(=O)-(C6-C10 aryl); and the R8 may optionally be substituted by one or more substituents selected from the group consisting of: halogen, -CN, C1-C4 alkyl, C1-C4 alkoxy, 3-10 membered heterocyclic, -NR a R b -NHR c -C(=O)NR a R b n is selected from the following group: 0, 1, 2, 3 or 4;

[0025] Among them, R a and R b Each is independently H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkyl-C6-C10 aryl, or R a and R b Together with the nitrogen atom attached to it, they form a 5-6 membered nitrogen heterocycle.

[0026] In another preferred embodiment, the SSAO small molecule inhibitor has the structure shown in Formula I-1, or a stereoisomer or racemate thereof:

[0027]

[0028] The definitions of R and B are as described in Equation I.

[0029] In another preferred embodiment, the SSAO small molecule inhibitor has a structure as shown in Formula I, I-1, or a stereoisomer or racemate thereof:

[0030] Where R is

[0031] B is a 6-membered heteroaromatic ring; wherein the heteroaromatic ring contains 1-2 nitrogen heteroatoms;

[0032] R7 is a 4-6 membered heterocycle containing one oxygen atom; and L3 is a substituted or unsubstituted 6-10 membered heterocycle containing 1-2 nitrogen heteroatoms, wherein the heterocycle is a monocyclic, fused, spirocyclic, or bridged ring.

[0033] Or R7 is selected from the following group: H, C1-C6 alkoxy, and L3 is selected from the following group: substituted or unsubstituted 6-10 membered bridged rings containing 1-2 nitrogen atoms, or 6-10 membered oxygen-containing spirocyclic heterocycles;

[0034] L3 can be optionally replaced by one or more R9s;

[0035] R9s are each independently selected from the following group: H, halogens, -CN, C1-C6 alkyl; or two R9s located on the same or different atoms are linked together to form a 4-8 membered ring.

[0036] In some preferred embodiments, L3 is a structure selected from the group consisting of:

[0037] The aforementioned The L3 refers to the connection site between the L3 and the B ring, and R7 is connected to other atoms on the L3 ring; and the L3 may optionally be replaced by one or more R9s; each R9 is independently selected from the group consisting of: H, halogens, -CN, C1-C6 alkyl.

[0038] In another preferred embodiment, the SSAO small molecule inhibitor has a structure as shown in Formula I and I-1.

[0039] Wherein, B is a pyridine ring or a pyrimidine ring.

[0040] In some preferred embodiments, the SSAO inhibitor is a compound having the structure shown in Formula I-2, or a stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof:

[0041]

[0042] R9 is selected from the following group: H, halogen, -CN, C1-C6 alkyl, or two R9s linked together to form a ring; z is 0, 1, 2, 3 or 4; and R7 is a 4-6 membered heterocycle containing 1 oxygen atom.

[0043] In some preferred embodiments, in the compounds of formula II-1 and I-2, R7 is In this context, p and q are each independently 0, 1, or 2.

[0044] In some preferred embodiments, in the compounds of formula I-1 and I-2, R7 is... p = 1, q = 1.

[0045] In another preferred embodiment, the SSAO small molecule inhibitor includes, but is not limited to, the following: TERN-201, PXS-4159, PXS-4728 (BI 1467335), PXS-4681, LJP1586, SzV-1287, U-V002, BTT2027, BTT2052, hydralazine hydrochloride, LJP1207, ECC0509, TT-01025, ASP8232, PRX167700, LG303174, PXS-4699, PXS-5370, PXS-5131, NN-6561, VX-01, BTT-1023, RTU-007, RTU-009, RTU-1096, UD-014, AoC3 inhibitor (Faron). Pharmaceuticals, or combinations thereof.

[0046] In another preferred embodiment, the SSAO small molecule inhibitor is TERN-201.

[0047] In another preferred embodiment, the SSAO small molecule inhibitor is PXS-4728 (BI 1467335).

[0048] In another preferred embodiment, the SSAO small molecule inhibitor is ECC0509.

[0049] In another preferred embodiment, the SSAO inhibitor includes, but is not limited to, the following monoclonal antibodies: vepalimomab, vapaliximab, Timolumab (BTT1023), or combinations thereof.

[0050] In another preferred embodiment, the SSAO inhibitor includes, but is not limited to, the following peptide: 68Ga-DOTA-Siglec-9.

[0051] In another preferred embodiment, the SSAO inhibitor is a compound having the structure shown in the following formula, or a stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof:

[0052]

[0053]

[0054]

[0055] In another preferred embodiment, the GLP-1 receptor agonist is selected from the group consisting of synthetic peptides, recombinant peptides, fusion proteins, recombinant proteins, monoclonal antibodies, and small molecule drugs.

[0056] In another preferred embodiment, the GLP-1 receptor agonist includes, but is not limited to, the following: exenatide, beinaglutide, liraglutide, loxenatide, PEG-Loxenatide, semaglutide, albiglutide, dulaglutide, lixisenatide, and tirzepatide. ide), Mazdutide, Supaglutide, Albanatide, Ecnoglutide, Efpeglenatide, Retatrutide, Survodutide, Exendin-4Fc fusion protein, Froniglutide, GZR-18, NLY-01, Noiiglutide, PF-1801, BPI-3016, Exenatide (Nano Precision), KN-056, Utreglutide, VTC-G15, ZT002, AER-601, Dance-601, DD-02, DD02S, DT-109, MW N105, MWN109, rHSA-GLP-1, SN-006, SPN009, ZT-005, ZT-006, AM-2149, NPM-159, AZD-0186, CellBead Cardio(BTG Ltd.), CJC-1131, CM3, LY-548806, MEDI-7219, NN-9928, LY-2428757, PF-4603629, ROSE-010, Taspoglutide, TH -0318, ZYOG-1, AC-3174, BEM-012, BK-0086, BRX-0585, CGEN-G11, CNTO-3649, CW-7213, E-2-HAS, GSK-2374697, HSP-00 1. HSP-004, HTI-2088, HYBR-011, JNASE-7001, Liraglutide-depot, LP-9, NB-1001, NN-9926, NN-9927, NNC0113-2023, ORG-249305, PB-1023, PF-4856883, RGT-028, RPC-8844, SHR-2042, SKL-18287, SXGLP1, YH-GLP1, ZY-D1 or their biosimilars, or combinations thereof.

[0057] In another preferred embodiment, the GLP-1 receptor agonist is loxenatide.

[0058] In another preferred embodiment, the GLP-1 receptor agonist is semaglutide.

[0059] In another preferred embodiment, the GLP-1 receptor agonist is dulaglutide.

[0060] In another preferred embodiment, the GLP-1 receptor agonist is liraglutide.

[0061] In another preferred embodiment, the GLP-1 receptor agonist is exenatide.

[0062] In another preferred embodiment, the GLP-1 receptor agonist includes, but is not limited to, the following: recombinant humanized monoclonal antibody against human GLP-1 receptor (Glutazumab), TB-59-2, GB-214, or combinations thereof.

[0063] In another preferred embodiment, the GLP-1 receptor agonist includes, but is not limited to, the following: Orforglipron (LY-3502970), NA-931, Danuglipron, HRS-7535, K-833, RGT-075, VCT220, GSBR-1290, MDR-001, CT-966, CT-996, ECC-5004, HDM1002, ID-110521156, Lotiglipron (PF-070) 81532), PF-06954522, SAL-0112, TERN-601, THDBH110, XW-014, TY705, BEBT-808, HNC1031, MLX-7000, PGN-OB2, RGT-274, TT-OAD2, TTP-273, AST-6055, Boc-5, FP-005, HD-7671, NNC-92041706, TTP-054, RGT-1383, or combinations thereof.

[0064] In another preferred embodiment, the GLP-1 receptor agonist is a compound having the structure shown in the following formula, or a stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof:

[0065]

[0066]

[0067] In another preferred embodiment, the drug combination comprises an SSAO inhibitor and a GLP-1 receptor agonist, and optionally a pharmaceutically acceptable carrier.

[0068] In another preferred embodiment, the pharmaceutical combination comprises an SSAO inhibitor pharmaceutical composition and a GLP-1 receptor agonist pharmaceutical composition, the pharmaceutical composition comprising an active ingredient and a pharmaceutically acceptable carrier.

[0069] In another preferred embodiment, the pharmaceutical combination is a pharmaceutical composition comprising an SSAO inhibitor and a GLP-1 receptor agonist, and a pharmaceutically acceptable carrier.

[0070] In another preferred embodiment, the mass ratio of the SSAO inhibitor to the GLP-1 receptor agonist in the drug combination is 1-1000:1000-1.

[0071] In another preferred embodiment, the mass ratio of the SSAO inhibitor to the GLP-1 receptor agonist in the drug combination is 1-10:10-1.

[0072] In another preferred embodiment, the mass ratio of the SSAO inhibitor to the GLP-1 receptor agonist in the drug combination is 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 20:1, 30:1, 40:1, 50:1, 60:1, 70:1, 80:1, 90:1, 100:1, 150:1, 200:1, 250:1, 300:1, 350:1, 400:1, 450:1, 500:1, 550:1, 600:1, 650:1, 700:1, 750:1, 800:1, 850:1, 900:1, 950:1, or 1000:1.

[0073] In another preferred embodiment, the mass ratio of the SSAO inhibitor to the GLP-1 receptor agonist in the drug combination is 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80, 1:90, 1:100, 1:150, 1:200, 1:250, 1:300, 1:350, 1:400, 1:450, 1:500, 1:550, 1:600, 1:650, 1:700, 1:750, 1:800, 1:850, 1:900, 1:950, or 1:1000.

[0074] A second aspect of the present invention provides a medicine kit, the medicine kit comprising:

[0075] (A) A therapeutically effective dose of SSAO inhibitors;

[0076] (B) A therapeutically effective dose of a GLP-1 receptor agonist; and

[0077] (C) Instruction manual.

[0078] A third aspect of the invention provides the use of a pharmaceutical combination as described in the first aspect of the invention, or a cassette as described in the second aspect of the invention, said pharmaceutical combination or cassette for preparing a pharmaceutical preparation for treating diseases selected from the group consisting of: liver inflammation, liver fibrosis, liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity, pancreatitis, hypertension, syndrome X, dyslipidemia, cognitive impairment, atherosclerosis, myocardial infarction, coronary heart disease and other cardiovascular diseases, stroke, inflammatory bowel syndrome, dyspepsia, gastric ulcer, diabetic complications, overweight, hyperlipidemia, hypercholesterolemia, atherosclerosis, coronary heart disease, congestive heart failure, arrhythmia, cerebral infarction, dementia, Parkinson's disease, and diabetic nephropathy.

[0079] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0080] Figure 1 Example 1: Changes in fasting blood glucose in animals. Two-way ANOVA: ** p<0.01 vs. normal group *** p<0.001 vs. normal group ## p<0.01 vs. model group ### p<0.001 vs. model group.

[0081] Figure 2 Example 1: Liver NAS total score. Kruskal-Wallis test: ￡￡￡ p<0.001 vs. normal group δ P<0.05 vs. model group δδ P<0.01 vs. model group.

[0082] Figure 3 Example 1: Percentage of liver fibrosis. Dunnett's test: $$ p<0.01 vs. normal group &p<0.05 vs. model group; Pairwise t-test: Ψ p<0.05 vs. semaglutide - 10 nmol / kg.

[0083] Figure 4 Example 1: Percentage decrease in liver fibrosis.

[0084] Pairwise t-test: Ψ p<0.05 vs. semaglutide - 10 nmol / kg.

[0085] Figure 5 Example 2. Endpoint: Serum ALT level. Kruskal-Wallis test: *** p<0.001 vs. G-1 # p<0.05vs.G-2; Pairwise t-test: $ p<0.05 vs. G-3.

[0086] Figure 6 Example 2. Endpoint: Serum AST level. Kruskal-Wallis test: *** p<0.001 vs. G-1 # p<0.05vs.G-2; Pairwise t-test: $ p<0.05 vs. G-3.

[0087] Figure 7 Example 2: NAS scoring. Kruskal-Wallis test: *** p<0.001 vs. G-1, # p<0.05 vs. G-2.

[0088] Figure 8 Example 2: Hepatocellular degeneration scoring. Kruskal-Wallis test: ** p<0.01 vs. G-1, # p<0.05 vs. G-2.

[0089] Figure 9 Example 2. Hepatocellular necrosis scoring. Kruskal-Wallis test: * p<0.05 vs. G-1, # p<0.05 vs. G-2.

[0090] Figure 10 Example 2: Total Liver Injury Score. Kruskal-Wallis test: ***p<0.001 vs. G-1, # p<0.05 vs. G-2, ## p<0.01 vs. G-2.

[0091] Figure 11 Example 2: Semi-quantitative scoring of liver fibrosis. Kruskal-Wallis test: *** p<0.01 vs. G-1 # p<0.05vs.G-2; Pairwise t-test: p<0.05vs.G-3.

[0092] Figure 12 Example 2: Percentage of liver fibrosis area. Kruskal-Wallis test: *** p<0.01vs.G-1, p=0.091vs.G-2. Detailed Implementation

[0093] Through long-term and in-depth research, the inventors discovered that the combination of SSAO inhibitors and GLP-1 receptor agonists exhibits superior therapeutic efficacy at the same dosage for metabolic-related diseases, particularly non-alcoholic fatty liver disease (NAFLD), especially non-alcoholic steatohepatitis (NASH). Based on these findings, the inventors completed this invention.

[0094] the term

[0095] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0096] As used herein, when referring to a specific enumerated value, the term “about” means that the value can vary by no more than 1% from the enumerated values. For example, as used herein, the expression “about 100” includes all values ​​between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0097] As used herein, the terms “containing” or “including (comprise)” can be open-ended, semi-closed, or closed. In other words, the terms also include “consistently made of” or “composed of”.

[0098] As used herein, the term “room temperature” or “normal temperature” refers to a temperature of 4–40°C, preferably 25 ± 5°C.

[0099] In the context of this specification, the term "administering" and variations thereof (including "administer" and "administration") include contacting, applying, delivering, or providing a compound or composition of the invention to a living organism or surface by any suitable means. In the context of this specification, the term "treatment" means any and all uses for treating a disease state or symptom in any way, preventing the establishment of a disease, or otherwise preventing, hindering, delaying, or reversing the progression of a disease or other undesirable symptom.

[0100] A “drug combination” can be a combination of two or more active ingredients; it can also be a combination of drug compositions prepared from various active ingredients individually, such as a combination of tablets and injections, a combination of capsules and injections, a combination of tablets and tablets, or a combination of tablets and capsules; it can also be a drug composition prepared by combining various active drugs.

[0101] The term "active ingredient" or "active drug" in the context of pharmaceutical combinations according to the invention refers to the SSAO inhibitor and / or GLP-1 receptor agonist according to the invention.

[0102] The term "SSAO" within the scope of this invention refers to an aminourea-sensitive amine oxidase (SSAO) enzyme (also known as primary amine oxidase, plasma amine oxidase, and benzylamine oxidase) that is structurally identical to vascular adhesion protein-1 (VAP-1). Within the scope of this invention, SSAO is used to describe the aminourea-sensitive amine oxidase (SSAO) enzyme.

[0103] The term "SSAO inhibitor" within the scope of this invention refers to compounds that exhibit inhibitory effects on aminourea-sensitive amine oxidase (SSAO), particularly human SSAO, and the term "SSAO inhibitor" also includes any pharmaceutically acceptable salt, prodrug, hydrate, and solvate thereof, including their respective crystalline or polymorphic forms.

[0104] The term "GLP-1" within the scope of this invention refers to glucagon-like peptide-1, a hormone produced by intestinal cells.

[0105] The term "GLP-1 receptor agonist" within the scope of this invention refers to compounds that can exert an incretin effect by activating glucagon-like peptide-1 receptors, also known as "GLP-1RA" or "GLP-1RAs". This includes synthetic peptides, recombinant peptides, fusion proteins, recombinant proteins, monoclonal antibody GLP-1 receptor agonists, and small molecule GLP-1 receptor agonists.

[0106] "Drug combination therapy," "combination therapy," "combination treatment," "combination medication," or "combination therapy" refers to drug treatment achieved by combining or mixing more than one active ingredient. For example, the combination of an SSAO inhibitor and a GLP-1 receptor agonist used in this article, where their respective symptoms and manifestations constitute combination therapy. "Combination" administration means that two drugs (such as the SSAO inhibitor or GLP-1 receptor agonist used in this article) are administered in any manner in which the pharmacological effects of both drugs are simultaneously manifested in the patient. Therefore, combination administration does not require the use of a single drug composition, the same dosage form, or even the same route of administration for the two drugs, or for the two drugs to be administered exactly simultaneously. The two drugs can be administered simultaneously, sequentially, or alternately. The two drugs can also be formulated into a single pharmaceutically acceptable composition. Non-limiting examples of such single compositions are oral compositions or oral dosage forms.

[0107] "Patient" refers to a mammal, including both humans and non-human mammals. Examples of patients include, but are not limited to, mice, rats, hamsters, guinea pigs, pigs, rabbits, cats, dogs, goats, sheep, cattle, and humans. In some implementations, "patient" refers to a human.

[0108] "Pharmaceutical acceptable" means safe and non-toxic, preferably for internal use, and more preferably for human use.

[0109] The term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0110] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the bioavailability of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobroms, sulfates, nitrates, and phosphates; organic acid salts include, but are not limited to, formates, acetates, 2,2-dichloroacetate, trifluoroacetate, propionates, hexanoates, octanoates, decanoates, undecenoates, glycolates, gluconates, lactates, sebates, adipates, glutarate, malonates, oxalates, maleates, succinates, fumarates, tartrates, citrates, palmitates, stearates, oleates, cinnamates, laurates, malates, glutamates, pyroglutamates, aspartate, benzoates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, alginates, ascorbic acid salts, salicylates, 4-aminosalicylic acid salts, and naphthalene disulfonates. These salts can be prepared using methods known in this field.

[0111] "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that retain the bioavailability of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, the following: primary amines, secondary amines, and tertiary amines; substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. These salts can be prepared by methods known in the art.

[0112] The compounds described herein may contain one or more chiral centers. In such cases, the description or naming of a particular stereoisomer means that the indicated stereocenter has a specified stereochemistry, wherein it should be understood that, unless otherwise specified, a small number of other stereoisomers may also exist, provided that the utility of the described or named compound is not eliminated by the presence of another stereoisomer.

[0113] application

[0114] Because the drug combinations of the present invention have excellent therapeutic effects on non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredients can be used for the prevention and / or treatment of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

[0115] In this application, the term "pharmaceutical composition" refers to a formulation of the compounds of the present invention with a medium generally accepted in the art for delivering bioactive compounds to mammals (e.g., humans). This medium includes pharmaceutically acceptable carriers. The purpose of a pharmaceutical composition is to facilitate administration to the organism, thereby promoting the absorption of the active ingredient and the exertion of its bioactivity.

[0116] In this application, the term "pharmaceutical acceptable" means a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, i.e., the substance can be administered to an individual without causing an adverse biological reaction or interacting adversely with any component contained in the composition.

[0117] In this application, the term "pharmaceuticalally acceptable excipient" includes, but is not limited to, any adjuvant, carrier, excipient, flow aid, sweetener, diluent, preservative, dye / coloring agent, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that is permitted by the relevant government regulatory authority to be acceptable for human or livestock use.

[0118] In this application, the terms “preventive,” “prevention,” and “avoidance” include reducing the likelihood of a patient developing or worsening a disease or symptom.

[0119] In this application, the term "treatment" and other similar synonyms include the following meanings:

[0120] (i) To prevent the occurrence of disease or condition in mammals, especially when such mammals are susceptible to the disease or condition but have not yet been diagnosed with it;

[0121] (ii) To suppress a disease or symptom, that is, to curb its development;

[0122] (iii) Relieve the disease or symptom, even if the condition of the disease or symptom subsides; or

[0123] (iv) To alleviate the symptoms caused by the disease or condition.

[0124] In this application, the terms "effective amount," "therapeutic effective amount," or "pharmaceutical effective amount" refer to an amount of at least one drug or compound that, when taken orally, is sufficient to alleviate to some extent one or more symptoms of the disease or condition being treated. The result may be a reduction and / or relief of signs, symptoms, or causes, or any other desired change in a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising the compounds disclosed herein that is clinically necessary to provide significant symptom relief. Effective amounts suitable for any individual case can be determined using techniques such as dose escalation testing.

[0125] In this application, the terms “administer,” “apply,” “deliver,” etc., refer to methods capable of delivering a compound or composition to the desired site for biological action. These methods include, but are not limited to, oral administration, duodenal administration, parenteral administration (including intravenous, subcutaneous, intraperitoneal, intramuscular, intra-arterial injection or infusion), local administration, and rectal administration. Those skilled in the art are familiar with administration techniques that can be used with the compounds and methods described herein, such as those discussed in Goodman and Gilman, *The Pharmacological Basis of Therapeutics*, current ed.; *Pergamon*; and *Remingtonin Pharmaceutical Sciences* (current edition), Mack Publishing Co., Easton, Pa. In preferred embodiments, the compounds and compositions discussed herein are administered via oral administration and / or injection.

[0126] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably, 5-200 mg of the compound of the present invention per dose. Preferably, "one dose" is a capsule, tablet, or injection.

[0127] "Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gel substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds.

[0128] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

[0129] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier). In capsules, tablets, and pills, the dosage form may also contain a buffer.

[0130] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0131] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents, such as water or other solvents, solubilizers, and emulsifiers, as commonly used in the art.

[0132] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0133] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0134] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0135] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage administered is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose of the first drug is typically 1–2000 mg, preferably 5–500 mg; the daily dose of the second drug is typically 0.1–2000 mg, preferably 0.1–500 mg, more preferably 0.1–100 mg, and even more preferably 0.1–1 mg; or the weekly dose is 0.1–1000 mg, preferably 0.1–100 mg, and even more preferably 0.1–10 mg. Of course, the specific dosage should also consider factors such as the route of administration and the patient's health condition, which are all within the scope of a skilled physician's expertise.

[0136] The invention is further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions, such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0137] Example 1: Efficacy experiment of the compound in a NASH model induced by streptozotocin-high-fat (STZ-HFD) diet in C57BL / 6 mice.

[0138] Newborn C57BL / 6 pregnant rats were subcutaneously injected with streptozotocin (STZ, sc, 20 μL / rat, concentration 10 mg / mL) within 48 hours of birth, and nursed by their mothers for 3-4 weeks. Newborn male rats were not injected with STZ subcutaneously, and were nursed by their mothers for 3-4 weeks as normal control rats. After 3-4 weeks, model rats were selected and randomly divided according to animal weight and fasting blood glucose levels into a model group, an SSAO inhibitor group (compound 4, 6 mg / kg), a GLP-1 receptor agonist group (semaglutide, 10 nmol / kg), and a combination group receiving GLP-1 receptor agonist (semaglutide, 10 nmol / kg) and SSAO inhibitor (compound 4, 6 mg / kg). All groups were fed a high-fat diet (HFD). Six animals from the non-STZ-injected group were selected as a normal control group based on their weight and fasting blood glucose levels and fed a standard diet. Administering the high-fat diet began in the second week, once daily for 5 weeks. Animals were weighed twice a week after being fed a high-fat diet, and their food intake was recorded every two days. At the end of the experiment, peripheral blood was collected from the animals to prepare serum, and relevant indicators in the serum were detected. After euthanasia, the animals were perfused with hypothermic saline, and gross images of the liver were collected and weighed. A portion of the left lobe of the liver was flash-frozen in liquid nitrogen and stored at -80°C for liver indicator detection. The remaining liver tissue was fixed in 10% formalin for pathological examination.

[0139] Figure 1-Figure 4 The results showed that in the STZ+high-fat diet-induced NASH model, the semaglutide group improved fasting blood glucose levels, and this improvement was further enhanced when combined with an SSAO inhibitor. The semaglutide treatment group significantly reduced liver NAS scores, while the SSAO inhibitor treatment group significantly improved liver fibrosis. The combination of semaglutide and SSAO inhibitors significantly reduced liver NAS scores by improving hepatocellular steatosis and hepatocellular ballooning degeneration, and also reduced the percentage of liver fibrosis area. Furthermore, the percentage of liver fibrosis and the percentage reduction in liver fibrosis were significantly improved in this combination group compared to the semaglutide treatment group.

[0140] Overall experimental results indicate that the combined use of SSAO inhibitors and GLP-1 receptor agonists can enhance the efficacy against NASH and bring more comprehensive clinical benefits.

[0141] Example 2: Pharmacodynamic test of the compound in a mouse NASH model induced by a high-fat and CCL4 diet.

[0142] Normal male mice fed a standard diet were designated as the control group. Other male mice fed a high-fat diet were randomly assigned to control groups based on fasting blood glucose and body weight (≥40g was the inclusion criterion). The groups included a control group, a model group, an SSAO inhibitor group (compound 4, 6mg / kg), a GLP-1 receptor agonist group (semaglutide, 10nmol / kg), and a combination group receiving both GLP-1 receptor agonist (semaglutide, 10nmol / kg) and SSAO inhibitor (compound 4, 6mg / kg). Except for the control group, the other animals were administered CCL4 via gavage at a dose of 1mL / kg every two days for 4 weeks to induce a mouse NASH model. The control group received the solvent via gavage, while the treatment groups received the SSAO inhibitor via oral gavage and / or semaglutide via subcutaneous injection daily for 4 weeks. At the start of treatment, animal body weight and food intake were recorded every two days, and fasting blood glucose was recorded before and weekly after treatment. Twenty-eight days after drug administration, the experimental endpoint was determined by fasting serum biochemistry and serum ELISA analysis of relevant indicators. Liver tissue was collected, fixed in 10% formalin solution, and subjected to H&E and SR staining. Hepatocyte degeneration, hepatocyte necrosis, hepatocyte ballooning degeneration, inflammatory cell infiltration, and fatty degeneration were semi-quantitatively scored. Liver fibrosis was also semi-quantitatively scored, and the percentage of liver fibrosis area was calculated to determine the degree of liver fibrosis.

[0143] Figures 5-12 The results showed that oral administration of SSAO inhibitors alone significantly reduced NAS scores, total liver injury scores, and liver fibrosis with a trend towards improvement. Subcutaneous injection of semaglutide alone significantly reduced hepatocellular degeneration scores and total liver injury scores. Combined administration of oral SSAO inhibitors and subcutaneous injection of semaglutide significantly improved serum ALT and AST levels, significantly reduced hepatocellular degeneration, hepatocellular necrosis, NAS scores, and total liver injury scores, and also significantly reduced fibrosis scores. Compared with subcutaneous administration of semaglutide alone, the combined administration showed a more comprehensive efficacy, with greater improvement in serum ALT and AST levels and liver fibrosis indicators, and a more significant effect.

[0144] The results suggest the potential of combining semaglutide and SSAO inhibitors in the treatment of NASH.

[0145] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A drug combination, characterized in that, The drug combination includes: (A) A therapeutically effective dose of an SSAO inhibitor; and (B) Therapeutic effective dose of GLP-1 receptor agonist (GLP-1RA).

2. The pharmaceutical combination as described in claim 1, characterized in that, The SSAO inhibitors are selected from the group consisting of: small molecule SSAO inhibitors or pharmaceutically acceptable salts thereof, monoclonal antibodies or peptides.

3. The drug combination as described in claim 1, characterized in that, The SSAO small molecule inhibitor has the structure shown in Formulas I and II, or its stereoisomers or racemates: Wherein, R has a structure selected from the group consisting of: H, F, Cl, Br, -NO2, -OH, -CN, =O, or -(L1). m -R8; The L1 is selected from the following group: CH2, S(O), S(O)2, NHC(O), C(O), NH, O or S; B is selected from the group consisting of: substituted or unsubstituted C3-12 cycloalkyl groups (including monocyclic, fused, bridged, and spirocyclic groups), substituted or unsubstituted C6-C10 aromatic rings (including monocyclic and fused rings), substituted or unsubstituted 5-12 membered heteroaromatic rings (including monocyclic and fused rings), and substituted or unsubstituted 3-12 membered heterocycles (including monocyclic, fused, bridged, and spirocyclic groups); wherein the heteroaromatic ring or heterocycle further contains 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur; X is O or a chemical bond; R1 is selected from the following group: H, halogens; R2 is selected from the following group: H, halogens; R3 is selected from the following group: H, -NH2, C1-C4 alkyl; m is selected from the following group: 0, 1, 2, 3 or 4; R8 is selected from the following group: H, C1-C4 alkyl, C1-C4 alkoxy, -(CH2). n -C3-C8 cycloalkyl, C6-C10 aryl, 5-10 heteroaryl, -(CH2) n -3-10 heterocyclic group, -NR a R b -NHR c ; R c Selected from the group consisting of: -C(=O)-(C1-C4 alkyl), -C(=O)-(C6-C10 aryl); and the R8 may optionally be substituted by one or more substituents selected from the group consisting of: halogen, -CN, C1-C4 alkyl, C1-C4 alkoxy, 3-10 membered heterocyclic, -NR a R b -NHR c 、-C(=O)NR a R b n is selected from the following group: 0, 1, 2, 3 or 4; Among them, R a and R b Each is independently H, C1-C4 alkyl, C1-C4 haloalkyl, -C1-C4 alkyl-C6-C10 aryl, or R a and R b Together with the nitrogen atom attached to it, they form a 5-6 membered nitrogen heterocycle.

4. The pharmaceutical combination as described in claim 1, characterized in that, The SSAO inhibitors mentioned are small molecule inhibitors selected from, but not limited to, the following group: TERN-201, PXS-4159, PXS-4728 (BI 1467335), PXS-4681, LJP1586, SzV-1287, U-V002, BTT2027, BTT2052, hydralazine hydrochloride, LJP1207, ECC0509, TT-01025, ASP8232, PRX167700, LG303174, PXS-4699, PXS-5370, PXS-5131, NN-6561, VX-01, BTT-1023, RTU-007, RTU-009, RTU-1096, UD-014, or combinations thereof; Alternatively, the SSAO inhibitor may be a monoclonal antibody selected from, but not limited to, the following group: vepalimomab, vapaliximab, Timolumab (BTT1023), or a combination thereof; Alternatively, the SSAO inhibitor is a polypeptide selected from, but not limited to, the following group: 68Ga-DOTA-Siglec-9; Preferably, the SSAO inhibitor is a compound having the structure shown in the following formula, or a stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof:

5. The combination as described in claim 1, characterized in that, The GLP-1 receptor agonist is selected from the following group: synthetic peptides, recombinant peptides, fusion proteins, recombinant proteins, monoclonal antibodies, and small molecule compounds.

6. The combination as described in claim 1, characterized in that, The GLP-1 receptor agonist mentioned is selected from, but not limited to, the following group: exenatide, beinaglutide, liraglutide, loxenatide, PEG-Loxenatide, semaglutide, albiglutide, dulaglutide, lixisenatide, and tirzepatide. Mazdutide, Supaglutide, Albanatide, Ecnoglutide, Efpeglenatide, Retatrutide, Survodutide, Exendin-4Fc fusion protein, Froniglutide, GZR-18, NLY-01, Noiiglutide, PF-1801, BPI-3016, Exenatide (Nano Precision), KN-056, Utreglutide, VTC-G15, ZT002, AER-601, Dance-601, DD-02, DD02S, DT-109, MW N105, MWN109, rHSA-GLP-1, SN-006, SPN009, ZT-005, ZT-006, AM-2149, NPM-159, AZD-0186, CellBead Cardio(BTG Ltd.), CJC-1131, CM3, LY-548806, MEDI-7219, NN-9928, LY-2428757, PF-4603629, ROSE-010, Taspoglutide, TH -0318, ZYOG-1, AC-3174, BEM-012, BK-0086, BRX-0585, CGEN-G11, CNTO-3649, CW-7213, E-2-HAS, GSK-2374697, HSP-00 1. HSP-004, HTI-2088, HYBR-011, JNASE-7001, Liraglutide-depot, LP-9, NB-1001, NN-9926, NN-9927, NNC0113-2023, ORG-249305, PB-1023, PF-4856883, RGT-028, RPC-8844, SHR-2042, SKL-18287, SXGLP1, YH-GLP1, ZY-D1, or their biosimilars, or combinations thereof; Alternatively, the GLP-1 receptor agonist may be a monoclonal antibody selected from, but not limited to, the following group: Glutazumab, TB-59-2, GB-214, or a combination thereof; Alternatively, the GLP-1 receptor agonist may be a small molecule compound selected from, but not limited to, the following group: Orforglipron (LY-3502970), NA-931, Danuglipron, HRS-7535, K-833, RGT-075, VCT220, GSBR-1290, MDR-001, CT-966, CT-996, ECC-5004, HDM1002, ID-110521156, Lotiglipron (PF-0 7081532), PF-06954522, SAL-0112, TERN-601, THDBH110, XW-014, TY705, BEBT-808, HNC1031, MLX-7000, PGN-OB2, RGT-274, TT-OAD2, TTP-273, AST-6055, Boc-5, FP-005, HD-7671, NNC-92041706, TTP-054, RGT-1383, or combinations thereof; Preferably, the GLP-1 receptor agonist is a compound having the structure shown in the following formula, or a stereoisomer or racemate thereof, or a pharmaceutically acceptable salt thereof:

7. The drug combination according to any one of claims 1-6, characterized in that, It contains SSAO inhibitors and GLP-1 receptor agonists, and optionally pharmaceutically acceptable carriers.

8. The pharmaceutical combination according to any one of claims 1-7, characterized in that, The mass ratio of the SSAO inhibitor to the GLP-1 receptor agonist is 1-1000:1000-1; preferably, the mass ratio of the SSAO inhibitor to the GLP-1 receptor agonist is 1-10:10-1.

9. A medicine kit, characterized in that, The medicine box includes: (A) A therapeutically effective dose of SSAO inhibitors; (B) A therapeutically effective dose of a GLP-1 receptor agonist; and (C) Instruction manual.

10. The use of the pharmaceutical combination as claimed in claim 1, or the pillbox as claimed in claim 9, characterized in that, The drug combination or kit is used to prepare a pharmaceutical preparation for treating diseases selected from the group consisting of: liver inflammation, liver fibrosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity, pancreatitis, hypertension, syndrome X, dyslipidemia, cognitive impairment, atherosclerosis, myocardial infarction, coronary heart disease and other cardiovascular diseases, stroke, inflammatory bowel syndrome, dyspepsia, gastric ulcer, diabetic complications, overweight, hyperlipidemia, hypercholesterolemia, atherosclerosis, coronary heart disease, congestive heart failure, arrhythmia, cerebral infarction, dementia, Parkinson's disease, and diabetic nephropathy.

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