Use of complement factor b inhibitor in preparation of drug for treating or preventing iga nephropathy or disease or condition related thereto

Abstract

Provided is use of a complement factor B inhibitor in the preparation of a drug for treating or preventing IgA nephropathy or a disease or condition related thereto. Specifically, provided is use of a compound represented by formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof in the preparation of a drug for treating or preventing IgA nephropathy or a disease or condition related thereto. The drug can effectively reduce creatinine and urea nitrogen levels in patients with IgA nephropathy, reduce renal inflammation and / or fibrosis in patients with IgA nephropathy, and provide a novel, effective and safe option for the treatment of IgA nephropathy.

Description

Use of complement factor B inhibitors in the preparation of medicines for the treatment or prevention of IgA nephropathy or related diseases or conditions. Technical Field

[0001] This invention belongs to the field of biomedicine, specifically relating to the use of a complement factor B inhibitor in the preparation of a drug for IgA nephropathy or related diseases or conditions. Background Technology

[0002] The complement system is part of the host's innate immune system, involved in lysing exogenous cells, enhancing antigen phagocytosis, agglutinating antigen carriers, and attracting macrophages and neutrophils. It is a crucial component of the body's innate immune system, responsible for resisting infections from exogenous pathogens, bacteria, and parasites. Furthermore, the complement system is a vital link between innate and adaptive immunity. The complement system comprises intrinsic complement components and various regulatory proteins. Intrinsic complement components include C1–C9, with C3 being the most abundant. The complement system is primarily activated through three pathways: the classical pathway (CP), the lectin pathway (LP), and the alternative pathway (AP).

[0003] In healthy individuals under normal physiological conditions, the complement pathway remains at a low level of activation to monitor for invasion by foreign pathogens. Complement proteins are distributed on the surface of apoptotic cells, and complement activation is strictly regulated, serving only to eliminate apoptotic cells without further activating other innate or adaptive immune responses. In the event of infection by foreign pathogens, the complement system is fully activated, producing inflammatory responses, opsonization, or phagocytosis, destroying pathogens and ultimately activating adaptive immune responses. Both inefficient and excessive complement stimulation can be harmful to the human body and are associated with increased susceptibility to infectious and non-infectious diseases. Complement dysfunction or overactivation has been linked to certain autoimmune, inflammatory, and neurodegenerative diseases, as well as ischemia-reperfusion injury and cancer. For example, IgA nephropathy (IgAN).

[0004] The pathogenesis of IgA nephropathy is not fully understood, but the currently accepted theory is the "multiple hit" hypothesis: (1) a significant increase in the synthesis of low-glycosylated IgA1 (Gd-IgA1) in the bloodstream; (2) the production of autoantibodies against Gd-IgA1 molecules; (3) the formation of circulating immune complexes containing pathogenic Gd-IgA1; and (4) the deposition of these complexes in the glomerular mesangial area, leading to glomerular mesangial cell activation and glomerular damage. Therefore, IgA nephropathy is widely considered a complex disease involving multiple genes and factors, and there is a huge clinical need for treatment worldwide.

[0005] In recent years, treatments targeting the etiology of IgA nephropathy have included traditional and novel corticosteroids, as well as traditional immunosuppressants and complement inhibitors. While these treatments have shown some efficacy, traditional corticosteroids can cause side effects such as increased risk of infection, cataracts, osteoporosis, fractures, and coronary artery disease. Even with novel corticosteroids (such as budesonide released in the gut), the safety and efficacy require further clinical validation. Traditional immunosuppressants, such as cyclophosphamide, are associated with increased risks of premature ovarian failure, hemorrhagic cystitis, bladder and other malignancies, leukopenia, and increased infection risk. New complement inhibitors, such as eculizumab, are relatively new to the market, and their efficacy and associated risks remain unclear. Furthermore, their high cost places a significant burden on patients. Therefore, developing a new drug for treating IgA nephropathy is of significant clinical importance.

[0006] WO2024149261A1 discloses a series of complement factor B inhibitors, and specifically discloses compounds with the following Formula I structure: Summary of the Invention

[0007] On one hand, the present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof in the preparation of a medicament for the treatment or prevention of IgA nephropathy or related diseases or conditions.

[0008] In one embodiment of the invention, the use includes reducing creatinine and / or blood urea nitrogen levels, particularly serum creatinine and / or blood urea nitrogen levels, in patients with IgA nephropathy.

[0009] In one embodiment, the creatinine level decreases by at least 5%, for example, 10%, four weeks after administration of the compound or its pharmaceutically acceptable salt or hydrate. In another embodiment, the creatinine level decreases by at least 10%, for example, 20%, eight weeks, for example, twelve weeks, after administration of the compound or its pharmaceutically acceptable salt or hydrate.

[0010] In one embodiment, the level of urea nitrogen decreases by at least 5%, for example, 10%, after 4 weeks of administration of the compound or its pharmaceutically acceptable salt or hydrate. In another embodiment, the level of urea nitrogen decreases by at least 10%, for example, 20%, after 8 weeks, for example, 12 weeks, of administration of the compound or its pharmaceutically acceptable salt or hydrate.

[0011] In one embodiment of the invention, the use includes reducing proteinuria in patients with IgA nephropathy.

[0012] In one embodiment, the total urinary protein level (mg / 24h) in the patient decreases by at least 5%, for example, 10%, after 4 weeks of administration of the compound or its pharmaceutically acceptable saline or hydrate. In another embodiment, the total urinary protein level (mg / 24h) in the patient decreases by at least 10%, for example, 20%, 30%, 40%, or even 50%, after 8 weeks, for example, 12 weeks of administration of the compound or its pharmaceutically acceptable saline or hydrate.

[0013] In one embodiment of the invention, the use includes reducing the urine protein-to-creatinine ratio in patients with IgA nephropathy.

[0014] In one embodiment, the urinary protein creatinine ratio in the patient is reduced by at least 10%, such as 20% or 30%, four weeks after administration of the compound or its pharmaceutically acceptable salt or hydrate thereof. In another embodiment, the urinary protein creatinine ratio in the patient is reduced by at least 10%, such as 20%, 30%, 40%, or even 50%, eight weeks after administration of the compound or its pharmaceutically acceptable salt or hydrate thereof, such as twelve weeks.

[0015] In one embodiment of the invention, the use includes inhibiting the proliferation of glomerular mesangial cells in patients with IgA nephropathy.

[0016] In one embodiment of the invention, the use includes reducing kidney inflammation and / or fibrosis in patients with IgA nephropathy.

[0017] In one embodiment of the invention, the use includes reducing IgA deposition in the glomeruli of patients with IgA nephropathy.

[0018] In one embodiment of the invention, the use is in the preparation of a medicament for the treatment or prevention of primary IgA nephropathy or related diseases or conditions.

[0019] In one embodiment of the invention, the compound or its pharmaceutically acceptable salt or hydrate is used to treat diseases or conditions associated with IgA nephropathy, such as hematuria, proteinuria, albuminuria, hypertension, early kidney disease, nephrotic syndrome (e.g., protein loss of 3-3.5 grams in urine), acute renal failure, chronic renal failure, and advanced chronic kidney disease (CKD).

[0020] In one embodiment of the present invention, the IgA nephropathy is primary IgA nephropathy in adults. In one embodiment of the present invention, the IgA nephropathy is IgA nephropathy with crescentic glomerulonephritis. In one embodiment of the present invention, the IgA nephropathy is pediatric IgA nephropathy. In one embodiment of the present invention, the IgA nephropathy is post-transplant IgA nephropathy.

[0021] In one embodiment of the present invention, the patient's 24h-UPE ≥ 0.75g / 24h, or FMV UPCR ≥ 0.8g / g.

[0022] In one embodiment of the invention, the patient's 24h-UPE is ≥0.75g / 24h for a period of more than 2 weeks.

[0023] In one embodiment of the present invention, the patient's eGFR is ≥30 ml / min / 1.73 m 2 .

[0024] In one embodiment of the invention, the patient's eGFR is ≥30 ml / min / 1.73 mcg for a period of time exceeding 2 weeks. 2 .

[0025] In one embodiment of the invention, the patient is intolerant to RAS blockers, or the 24h-UPE remains ≥0.75g / 24h after using RAS blockers.

[0026] In one embodiment of the present invention, the dosage of compound I is 0.1–2000 mg / time, specifically selected from 1 mg / time, 2.5 mg / time, 5 mg / time, 7.5 mg / time, 10 mg / time, 12.5 mg / time, 15 mg / time, 17.5 mg / time, 20 mg / time, 22.5 mg / time, 25 mg / time, 27.5 mg / time, 30 mg / time, 32.5 mg / time, 35 mg / time, 37.5 mg / time, 40 mg / time, 42.5 mg / time, 45 mg / time, etc. 47.5mg / dose, 50mg / dose, 52.5mg / dose, 55mg / dose, 60mg / dose, 65mg / dose, 70mg / dose, 75mg / dose, 80mg / dose, 85mg / dose, 90mg / dose, 95mg / dose, 100mg / dose, 105mg / dose, 110mg / dose, 120mg / dose, 130mg / dose, 140mg / dose, 150mg / dose, 160mg / dose, 170mg / dose, 180mg / dose, 190mg / dose, 200mg / dose g / dose, 210mg / dose, 220mg / dose, 230mg / dose, 240mg / dose, 250mg / dose, 260mg / dose, 270mg / dose, 280mg / dose, 290mg / dose, 300mg / dose, 350mg / dose, 400mg / dose, 450mg / dose, 500mg / dose, 550mg / dose, 600mg / dose, 700mg / dose, 750mg / dose, 800mg / dose, 900mg / dose, 1000mg / dose, 1200mg / dose, 15 00mg / dose, 1800mg / dose, 2000mg / dose, and any value between any two of the above (although not listed individually, they are considered to be explicitly stated); preferably 10 to 1000mg / dose; more preferably 50 to 700mg / dose; even more preferably 50 to 500mg / dose; even more preferably 50 to 400mg / dose; and even more preferably 50mg / dose, 100mg / dose, 150mg / dose, 200mg / dose, 250mg / dose, 300mg / dose, 350mg / dose, or 400mg / dose.

[0027] In one embodiment of the present invention, the dosage of compound I is 50 mg per dose.

[0028] In one embodiment of the present invention, the dosage of compound I is 100 mg / time.

[0029] In one embodiment of the present invention, the dosage of compound I is 150 mg per dose.

[0030] In one embodiment of the present invention, the dosage of compound I is 200 mg / time.

[0031] In one embodiment of the present invention, the dosage of compound I is 250 mg / time.

[0032] In one embodiment of the present invention, the dosage of compound I is 300 mg / time.

[0033] In one embodiment of the present invention, the dosage of compound I is 400 mg / time.

[0034] In one embodiment of the present invention, the administration frequency of the compound of formula I may be once a day, twice a day, three times a day, once a week, three times a week, once every two weeks, once every three weeks, or once a month; preferably once a day, twice a day, or three times a day.

[0035] In one embodiment of the present invention, the compound of formula I is administered once daily.

[0036] In one embodiment of the present invention, the compound of formula I is administered twice a day.

[0037] In one embodiment of the present invention, the dosage of compound I is 50 mg / time, and the frequency of administration is once a day.

[0038] In one embodiment of the present invention, the dosage of compound I is 100 mg / time, and the frequency of administration is once a day.

[0039] In one embodiment of the present invention, the dosage of compound I is 150 mg / time, and the frequency of administration is once a day.

[0040] In one embodiment of the present invention, the dosage of compound I is 200 mg / time, and the frequency of administration is once a day.

[0041] In one embodiment of the present invention, the dosage of compound I is 250 mg / time, and the frequency of administration is once a day.

[0042] In one embodiment of the present invention, the dosage of compound I is 300 mg / time, and the frequency of administration is once a day.

[0043] In one embodiment of the present invention, the dosage of compound I is 200 mg / time, and the frequency of administration is twice a day.

[0044] In one embodiment of the present invention, the dosage of compound I is 300 mg / time, and the frequency of administration is twice a day.

[0045] In one embodiment of the present invention, the dosage of compound I is 400 mg / time, and the frequency of administration is twice a day.

[0046] In one embodiment of the invention, the compound of formula I can be used alone or in combination with other therapeutic agents or methods for treating or preventing kidney diseases associated with complement bypass pathway activation, such as in combination with other C5 antibody inhibitors (eculizumab, revlizumab).

[0047] In one embodiment of the invention, the compound of formula I can be given to the patient as a free base, or as a pharmaceutically acceptable salt, hydrate, or prodrug (which will be converted into a free base in vivo).

[0048] On the other hand, the present invention also provides a method for preventing and / or treating IgA nephropathy or related diseases or conditions, comprising administering to a patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof.

[0049] On the other hand, the present invention also provides a method for preventing and / or treating primary IgA nephropathy or related diseases or conditions, comprising administering to a patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof.

[0050] On the other hand, the present invention also provides a method for reducing creatinine and / or blood urea nitrogen levels, particularly serum creatinine and / or blood urea nitrogen levels, in patients with IgA nephropathy, comprising administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof.

[0051] On the other hand, the present invention also provides a method for reducing proteinuria in patients with IgA nephropathy, comprising administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof.

[0052] On the other hand, the present invention also provides a method for reducing the urine protein-to-creatinine ratio in patients with IgA nephropathy, comprising administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof.

[0053] On the other hand, the present invention also provides a method for inhibiting the proliferation of glomerular mesangial cells in patients with IgA nephropathy, comprising administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof.

[0054] On the other hand, the present invention also provides a method for reducing renal inflammation and / or fibrosis in patients with IgA nephropathy, comprising administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof.

[0055] On the other hand, the present invention also provides a method for reducing IgA deposition in the glomeruli of patients with IgA nephropathy, comprising administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof.

[0056] On the other hand, the present invention also provides a method for preventing and / or treating IgA nephropathy or related diseases or conditions, comprising administering to a patient 0.1 to 2000 mg of a compound of formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof.

[0057] On the other hand, the present invention also provides a method for preventing and / or treating primary IgA nephropathy or related diseases or conditions, comprising administering 0.1 to 2000 mg of a compound of formula I or a pharmaceutically acceptable salt thereof or its hydrate to a patient.

[0058] On the other hand, the present invention also provides a method for reducing creatinine and / or blood urea nitrogen levels, especially serum creatinine and / or blood urea nitrogen levels, in patients with IgA nephropathy, comprising administering to the patient 0.1 to 2000 mg of a compound of formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof.

[0059] On the other hand, the present invention also provides a method for reducing proteinuria in patients with IgA nephropathy, comprising administering to the patient 0.1 to 2000 mg of a compound of formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof.

[0060] On the other hand, the present invention also provides a method for reducing the urine protein-to-creatinine ratio in patients with IgA nephropathy, comprising administering 0.1 to 2000 mg of a compound of formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof to the patient.

[0061] On the other hand, the present invention also provides a method for inhibiting the proliferation of glomerular mesangial cells in patients with IgA nephropathy, comprising administering 0.1 to 2000 mg of a compound of formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof to the patient.

[0062] On the other hand, the present invention also provides a method for reducing renal inflammation and / or fibrosis in patients with IgA nephropathy, comprising administering to the patient 0.1 to 2000 mg of a compound of formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof.

[0063] On the other hand, the present invention also provides a method for reducing IgA deposition in the glomeruli of patients with IgA nephropathy, comprising administering to the patient 0.1 to 2000 mg of a compound of formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof.

[0064] On the other hand, the present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof for the prevention and / or treatment of IgA nephropathy or related diseases or conditions.

[0065] On the other hand, the present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof for the prevention and / or treatment of primary IgA nephropathy or related diseases or conditions.

[0066] On the other hand, the present invention also provides a compound of formula I, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, for reducing creatinine and / or blood urea nitrogen levels, particularly serum creatinine and / or blood urea nitrogen levels in patients with IgA nephropathy.

[0067] On the other hand, the present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof for reducing proteinuria in patients with IgA nephropathy.

[0068] On the other hand, the present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof for reducing the urinary protein-to-creatinine ratio in patients with IgA nephropathy.

[0069] On the other hand, the present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof that inhibits the proliferation of glomerular mesangial cells in patients with IgA nephropathy.

[0070] On the other hand, the present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof that reduces renal inflammation and / or fibrosis in patients with IgA nephropathy.

[0071] On the other hand, the present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof for reducing IgA deposition in the glomeruli of patients with IgA nephropathy.

[0072] On the other hand, the present invention also provides a pharmaceutical composition for the prevention and / or treatment of IgA nephropathy or related diseases or conditions, said pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof.

[0073] On the other hand, the present invention also provides a pharmaceutical composition for the prevention and / or treatment of primary IgA nephropathy or related diseases or conditions, said pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof.

[0074] On the other hand, the present invention also provides a pharmaceutical composition for the prevention and / or treatment of IgA nephropathy or related diseases or conditions, said pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof, and one or more pharmaceutically acceptable carriers.

[0075] On the other hand, the present invention also provides a pharmaceutical composition for the prevention and / or treatment of primary IgA nephropathy or related diseases or conditions, said pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof, and one or more pharmaceutically acceptable carriers.

[0076] On the other hand, the present invention also provides a pharmaceutical composition for reducing creatinine and / or blood urea nitrogen levels, particularly serum creatinine and / or blood urea nitrogen levels, in patients with IgA nephropathy, said pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof, and one or more pharmaceutically acceptable carriers.

[0077] On the other hand, the present invention also provides a pharmaceutical composition for reducing proteinuria in patients with IgA nephropathy, the pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof, and one or more pharmaceutically acceptable carriers.

[0078] On the other hand, the present invention also provides a pharmaceutical composition for reducing the urine protein-to-creatinine ratio in patients with IgA nephropathy, said pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof, and one or more pharmaceutically acceptable carriers.

[0079] On the other hand, the present invention also provides a pharmaceutical composition for inhibiting the proliferation of glomerular mesangial cells in patients with IgA nephropathy, the pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof, and one or more pharmaceutically acceptable carriers.

[0080] On the other hand, the present invention also provides a pharmaceutical composition for reducing renal inflammation and / or fibrosis in patients with IgA nephropathy, the pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof, and one or more pharmaceutically acceptable carriers.

[0081] On the other hand, the present invention also provides a pharmaceutical composition for reducing IgA deposition in the glomeruli of patients with IgA nephropathy, said pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof, and one or more pharmaceutically acceptable carriers.

[0082] On the other hand, the present invention also provides the use of a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof and one or more pharmaceutically acceptable carriers in the preparation of a medicament for the prevention and / or treatment of IgA nephropathy or related diseases or conditions.

[0083] On the other hand, the present invention also provides the use of a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof and one or more pharmaceutically acceptable carriers in the preparation of a medicament for the prevention and / or treatment of primary IgA nephropathy or related diseases or conditions.

[0084] On the other hand, the present invention also provides the use of a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof and one or more pharmaceutically acceptable carriers in the preparation of a medicament for reducing creatinine and / or blood urea nitrogen levels, particularly serum creatinine and / or blood urea nitrogen levels, in patients with IgA nephropathy.

[0085] On the other hand, the present invention also provides the use of a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof and one or more pharmaceutically acceptable carriers in the preparation of a medicament for reducing proteinuria in patients with IgA nephropathy.

[0086] On the other hand, the present invention also provides the use of a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof and one or more pharmaceutically acceptable carriers in the preparation of a medicament for reducing the urinary protein-to-creatinine ratio in patients with IgA nephropathy.

[0087] On the other hand, the present invention also provides the use of a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof and one or more pharmaceutically acceptable carriers in the preparation of a medicament for inhibiting the proliferation of glomerular mesangial cells in patients with IgA nephropathy.

[0088] On the other hand, the present invention also provides the use of a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof and one or more pharmaceutically acceptable carriers in the preparation of a medicament for reducing renal inflammation and / or fibrosis in patients with IgA nephropathy.

[0089] On the other hand, the present invention also provides the use of a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof and one or more pharmaceutically acceptable carriers in the preparation of a medicament for reducing the deposition of IgA in the glomeruli of patients with IgA nephropathy.

[0090] The compound of Formula I of the present invention, or its pharmaceutically acceptable salt or hydrate thereof, may also be administered to patients or subjects requiring such treatment by any suitable route of administration, such as oral, parenteral, rectal, pulmonary or local administration. Attached Figure Description

[0091] Figures 1a and 1b show the serum creatinine (Figure 1a) and blood urea nitrogen (Figure 1b) levels of animals in each group at different time points before and after drug administration (MEAN±SEM, N=12; **P<0.01, ***P<0.001 vs G2 group at the same time point);

[0092] Figure 2 shows the total urinary protein levels of each group of animals at different time points before and after drug administration (MEAN±SEM, N=12; **P<0.01, ***P<0.001 vs G2 group at the same time point);

[0093] Figures 3a and 3b show the ratio of urinary protein to creatinine at different time points before and after drug administration (Figure 3a) and the uPCR inhibition rate at 8 weeks after drug administration (Figure 3b) for each group of animals (MEAN±SEM, N=12; *P<0.05, ***P<0.001vs G2);

[0094] Figure 4 shows representative H&E staining images of the kidneys of animals in each group (G1:a, G2:b, G3:c, G4:d, G5:e);

[0095] Figure 5 shows representative images of DAPI staining (blue, left column), IgA immunofluorescence staining (green, middle column), and Merge staining (right column) of the kidneys of each group of animals (G1: a, b, c, G2: d, e, f, G3: g, h, i, G4: j, k, l, G5: m, n, o).

[0096] Figure 6 shows the ratio of IgA immunofluorescence area to glomerular area in the kidneys of each group of animals (MEAN±SEM, N=12, ***P<0.001vs G2 group). Detailed Implementation

[0097] Related definitions

[0098] Unless otherwise specified, the following terms used in the specification and claims shall have the following meanings:

[0099] IgA nephropathy (also known as Berger's disease, IgA nephritis, IgAN, or conjoint glomerulonephritis) is one of the most common chronic glomerular diseases worldwide. The clinical manifestations of IgA nephropathy are highly heterogeneous, and in the early stages, there are often no specific symptoms. Many patients are diagnosed incidentally during routine urine tests when microscopic hematuria or proteinuria is discovered. As the disease progresses and substantial renal function is impaired, patients may exhibit a variety of signs and symptoms, including cola-colored or tea-colored urine due to increased red blood cells; recurrent gross hematuria following upper respiratory tract or other infections; lower abdominal pain; increased foamy urine due to increased proteinuria; and edema of the hands and feet and hypertension due to water and sodium retention. These manifestations are essentially closely related to a series of pathophysiological processes, including abnormally glycosylated IgA1, autoantibody formation, deposition of renal immune complexes, and the triggered inflammatory responses and renal function loss.

[0100] The classic presentation of this disease is seen in approximately 40–50% of cases, especially in younger patients, often presenting as paroxysmal gross hematuria, usually secondary to one to two days after a nonspecific upper respiratory tract infection, and is related to mucosal immune activation and IgA antibody production. These episodes can occur irregularly at intervals of several months. Although most patients have essentially normal renal function and their symptoms resolve spontaneously, a minority may develop acute renal failure. Another 20–30% of patients, mostly elderly, present only with asymptomatic microscopic hematuria and mild proteinuria, often diagnosed during systematic screening. In addition, a small number of patients may present with more severe clinical types such as nephrotic-range proteinuria, acute renal failure, or chronic renal failure. It is noteworthy that IgA nephropathy can also be accompanied by various systemic diseases, such as liver failure, celiac disease, rheumatic immune diseases, and HIV infection; therefore, it is important to rule out related comorbidities during the diagnostic process. Definitive diagnosis relies on a series of examinations, including urinalysis, blood biochemistry, imaging assessment, and, as the gold standard, renal biopsy pathology.

[0101] The term "dosage" as used herein refers to the amount of the active compound (free base). It is understood that when the compound is administered in a pharmaceutically acceptable form as a salt or hydrate, the amount is expressed as the active compound (free base). For example, when a 2 mg dose of Formula I compound is administered as a tablet containing a salt of Formula I compound, the tablet will contain the equivalent of 2 mg of the Formula I compound salt.

[0102] The term "salt" as used herein may exist alone or in mixtures with the free compounds of the present invention, and is preferably a pharmaceutically acceptable salt. "Pharmaceutically acceptable salt" refers to pharmaceutically commonly used acidic or basic salts, wherein acidic salts include conventional organic or inorganic acid salts, wherein organic acid salts include, but are not limited to, p-toluenesulfonate, maleate, citrate, or tartrate; wherein inorganic acid salts include, but are not limited to, hydrobromide, hydrochloride, sulfate, or phosphate, preferably hydrochloride, sulfate, or phosphate; and wherein basic salts include, but are not limited to, sodium, potassium, calcium, thiocholine, or diethylamine salts, preferably sodium or calcium salts.

[0103] The term "oral administration" as used in this article refers to the ingestion of drugs through oral administration, where the drugs are absorbed into the bloodstream via the gastrointestinal tract and then distributed throughout the body or act on specific organs.

[0104] The term "parenteral administration" as used in this article refers to administration methods that do not pass through the gastrointestinal tract, including subcutaneous injection, intramuscular injection, and intravenous injection.

[0105] The term "rectal administration" as used in this article refers to the method of delivering medication into the rectum through the anus, where the medication is absorbed into the bloodstream through the rectal mucosa.

[0106] The term "lung administration" as used in this article refers to the direct delivery of drugs into the lungs via inhalation, where the drugs are absorbed into the bloodstream through the alveoli.

[0107] The term "topical administration" as used in this article refers to administration of a drug by coating or applying it directly to the epidermal tissue, including the skin or mucous membranes of the mouth or vagina.

[0108] The term "effective dose" or "therapeutic effective dose" as used in this article refers to a sufficient amount of a non-toxic drug or agent that achieves the desired effect.

[0109] The terms "patient" and "subject" used in this article are used interchangeably and generally refer to humans, but may also include non-human animals.

[0110] The term "pharmaceutically acceptable carrier" as used in this article includes, but is not limited to, diluents, binders, disintegrants, and lubricants.

[0111] As used herein, “treatment” for IgA nephropathy or its related diseases or conditions means that, upon administration of the compound to a subject (e.g., a human) diagnosed with the condition and / or experiencing its related symptoms, one or more of the following effects are achieved: a reduction in symptom severity, a faster rate of recovery, or a delay in disease progression compared to not receiving the treatment. In practice, effective treatment can be assessed in various ways. For example, after effective treatment, renal biopsy tissue may show a reduction or disappearance of IgA immune complex deposition in the renal mesangial area under immunofluorescence or electron microscopy. Furthermore, a range of clinical and imaging examinations—such as urinalysis, blood biochemistry tests, iodophthalate clearance tests, or renal ultrasound, X-ray, and cystoscopy—can be used to monitor treatment response or assess whether IgA nephropathy-related symptoms (such as proteinuria, hematuria, etc.) have decreased or disappeared after treatment. Therefore, in the context of this application, “treatment” encompasses partial or complete remission, improvement, reduction, inhibition, or decrease in the severity and incidence of the disease, and may, to a certain extent, delay the progression and occurrence of one or more clinical manifestations, pathological features, or causes. The treatment regimen can be implemented in the following population groups: individuals who have not yet shown clear signs of IgA nephropathy but have high-risk factors; subjects who only show early signs of kidney disease; patients who have one or more diagnostic criteria; or patients who have been diagnosed with IgA nephropathy. Preferably, the treatment regimen is implemented in patients who have been diagnosed with IgA nephropathy.

[0112] As used in this article, “prevention” of IgA nephropathy or its related diseases or conditions means making the subject less likely to develop the disease or condition, i.e., reducing the risk of developing the disease.

[0113] The abbreviations used in this article have the following meanings:

[0114] BSA: Bovine serum albumin.

[0115] H&E staining: Hematoxylin-eosin staining method.

[0116] BID: Twice daily.

[0117] QD: Once a day.

[0118] 24h-UPE: 24-hour urine protein quantification.

[0119] FMV: First morning urine.

[0120] UPCR: Urine protein to urine creatinine ratio.

[0121] eGFR: Glomerular filtration rate.

[0122] MEAN±SEM: mean plus or minus standard deviation.

[0123] DAPI staining: DAPI, or 4',6-diamidinyl-2-phenylindole, is a fluorescent dye that binds strongly to DNA and is commonly used in fluorescence microscopy. Because DAPI can penetrate intact cell membranes, it can be used to stain both live and fixed cells.

[0124] Merge represents a graph: The basic meaning of the word "merge" is "to combine" or "to merge". In this article, "merge" refers to merging multiple images into one image, which can be interpreted as a "merged graph".

[0125] CKD-EPI: Chronic Kidney Disease Epidemiology Collaboration, is a formula used to estimate the glomerular filtration rate in adults.

[0126] ACYW135 group meningococcal polysaccharide vaccine, to prevent epidemic cerebrospinal meningitis caused by Neisseria meningitidis groups A, C, Y and W135.

[0127] RAS blockers: also known as angiotensin receptor blockers, including ACEi or ARB.

[0128] ACEi: Angiotensin-converting enzyme inhibitors (ACEIs).

[0129] ARB: Angiotensin II receptor antagonist (ARB).

[0130] SGLT2 inhibitors: Sodium-glucose cotransporter 2 inhibitors.

[0131] BMI: Body Mass Index = weight (kg) / height 2 (m2 )。

[0132] The following typical examples are used to illustrate the present invention. Simple substitutions or improvements made by those skilled in the art to the present invention all fall within the technical solutions protected by the present invention. Unless otherwise specified, the reagents used in the specific embodiments of the present invention are all known products and can be obtained by purchasing commercially available products.

[0133] Experimental Example 1: Pharmacodynamic study on the rat IgA nephropathy model

[0134] (1) Experimental materials

[0135] 1) Experimental animals: SD rats, SPF grade; body weight: 180 - 250 g; age: 6 - 8 weeks old, purchased from Vital River Laboratory Animal Technology Co., Ltd. Experimental animal production license: SCXK(Zhe)2019 - 0001; Experimental animal quality certificate: 20221116Aazz0619000593; Zhejiang, China.

[0136] 2) Experimental reagents: Tween 80 (Sigma, P4780), carbon tetrachloride (Enox), castor oil (Xilong Scientific, CAS - No.: 8001 - 79 - 4), methylcellulose (Sigma, M0262), bovine serum albumin (BSA) (Sigma, V900933), lipopolysaccharide (LPS) (Sigma, L2880), IgA antibody (Santa Cruz, sc - 373823), urinary protein quantification test kit (Nanjing Jiancheng, C035 - 2 - 1), creatinine (Cr) determination kit (Nanjing Jiancheng, C011 - 2 - 1).

[0137] 3) Experimental instruments: microplate reader (TECAN, Infinite M NANO), biochemical analyzer (Mindray, BS - 2000M). (2) Experimental method: The experimental period of this experiment is 151 days, including a 95 - day model - building period and a 56 - day drug - administration period.

[0138] 1) Model construction: BSA (100 mg / mL) was intragastrically administered once every other day at a dose of 1000 mg / kg; castor oil and carbon tetrachloride were mixed in a ratio of 3:1 and subcutaneously injected once a week at a volume of 0.3 mL / 100 g; lipopolysaccharide LPS (0.1 mg / mL) was injected via the tail vein once at a dosing volume of 0.15 mL / 100 g at weeks 2, 6, and 10 respectively.

[0139] 2) Grouping and administration: Based on the blood and urine test results after modeling, 48 model animals were randomly divided into the following 4 groups, with 12 animals in each group: G2-model group, G3-G5-compound group (20 mg / kg, 60 mg / kg, 180 mg / kg), and another 12 animals without modeling served as the G1-normal control group. All animals were administered by gavage twice daily. The normal group and model group were given the corresponding solvent (0.5% (w / v) methylcellulose + 0.5% (v / v) Tween 80 aqueous solution).

[0140] 3) Detection indicators: Body weight was measured once a week, and cage-side observation was conducted twice a day, once in the morning and once in the afternoon; serum was collected before modeling, after modeling, and at weeks 4 and 8 after drug administration for blood creatinine and blood urea nitrogen testing; at the same time, 24-hour urine was collected for urine protein and urine creatinine testing to assess proteinuria level (urine protein to creatinine ratio uPCR = urine protein / urine creatinine); pathological examination: at the experimental endpoint, rat kidneys were collected from euthanized animals, H&E staining was performed to assess glomerular inflammatory infiltration, and IgA immunofluorescence staining was performed to assess IgA deposition.

[0141] 4) Data Analysis: Experimental data were analyzed and compared using one-way or two-way ANOVA. A p-value < 0.05 was considered statistically significant. uPCR inhibition rate % = (pre-drug uPCR - post-drug uPCR) / pre-drug uPCR * 100%.

[0142] (3) Experimental Results

[0143] After modeling, the levels of creatinine and urea nitrogen in the blood of all model animals were significantly higher than those in the G1 normal group. During the treatment period, the levels of creatinine and urea nitrogen in the G2 model group remained stable at a high level. After 4 weeks of treatment with the three dose groups of compound I, the levels of creatinine and urea nitrogen decreased, and further decreased after 8 weeks (Figures 1a and 1b). After modeling, the 24-hour total protein content and protein-to-creatinine ratio in the urine of all model animals were significantly increased. During the treatment period, the levels of total protein and protein-to-creatinine ratio in the urine of the G2 model group remained stable at a high level. After 4 weeks of treatment, the total protein level in the urine of the three dose groups of compound I showed a slight decrease, and a significant decrease after 8 weeks, in a dose-dependent manner (Figure 2). After 4 weeks of treatment, the urinary protein-to-creatinine ratio in the three dose groups of compound I was significantly lower than that in the G2 model group, and the difference was statistically significant. After 8 weeks, the uPCR further decreased, and the difference was statistically significant. After 8 weeks of administration, the uPCR inhibition rates were 23%, 39%, and 48%, respectively, and the inhibition rate in the compound I treatment group was dose-dependent (Figures 3a and 3b, Table 1). Kidney H&E pathology results showed that after modeling, the G2 model group animals exhibited significant inflammatory cell infiltration in the mesangial area of ​​the glomeruli, mesangial expansion, narrowing of capillary loops, compression and narrowing of Bursal State, and severe inadequate opening of the Bursal State. With increasing dosage of compound I, inflammatory cell infiltration in the rat glomeruli decreased, and the Bursal State space and capillary loops enlarged accordingly (Figure 4). Kidney IgA immunofluorescence staining results showed significant IgA deposition in the mesangial area of ​​the glomeruli in the G2 model group animals after modeling. The glomerular IgA deposition in the three dosage groups of compound I was negatively correlated with the dosage; the higher the drug dosage, the less IgA was deposited. The statistical results of the ratio of IgA fluorescence area to glomerular area showed that the ratio of IgA fluorescence area in the three dosage groups of compound I was significantly lower than that in the G2 model group, and the difference was statistically significant (P < 0.001) (Figure 5, Figure 6, Table 2).

[0144] Table 1. Urinary protein-to-creatinine ratio and uPCR inhibition rate at different time points before and after drug administration in each group of animals (MEAN±SEM, N=12) Note: Urine protein-to-creatinine ratio: two-way ANOVA. * P<0.05, ** P<0.01, *** P < 0.001 vs G2 at the same time point; uPCR inhibition rate: one-way ANOVA, * P<0.05, ** P<0.01, *** P<0.001 vs G2

[0145] Table 2. Ratio of IgA immunofluorescence area to glomerular area in the kidneys of each group of animals (MEAN±SEM, N=12) Note: One-way ANOVA, ***P < 0.001 vs G2 group

[0146] (4) Experimental Conclusion

[0147] Under our laboratory conditions, a stable IgA nephropathy model was successfully induced in rats using BSA in combination with carbon tetrachloride and LPS. Continuous gavage administration of the test compound (Formula I) for 8 weeks significantly reduced proteinuria and IgA deposition in the glomeruli of IgA nephropathy rats, and the effect was dose-dependent.

[0148] Experimental Example 2: Phase II trial of compound I versus placebo for the treatment of primary IgA nephropathy

[0149] (1) Test drug: Formula I compound, specification 100mg.

[0150] (2) Research objective: To evaluate the efficacy, safety, pharmacokinetic and pharmacodynamic characteristics of compound I in treating patients with IgA nephropathy.

[0151] (3) Selection criteria:

[0152] 1) Age ≥ 18 years old, gender not limited;

[0153] 2) Weight ≥ 40kg, BMI between 15 and 38kg / m² 2 Between (including critical values);

[0154] 3) The patient has been diagnosed with primary IgA nephropathy by renal biopsy within 8 years prior to screening or during the screening period, and there are no known secondary causes (including but not limited to allergic purpura, systemic lupus erythematosus, etc.);

[0155] 4) During the screening period, at the V1 visit, the 24h-UPE is ≥0.75g / 24h, or the FMV UPCR is ≥0.8g / g; at the V2 visit, the 24h-UPE is ≥0.75g / 24h, or the FMV UPCR is ≥0.8g / g (one retest is allowed at the V2 visit, with a maximum interval of 2 weeks between the two samples, and the average 24h-UPE of the two samples must be ≥0.75g / 24h). The 24-hour urine collection interval between V1 and V2 must be ≥2 weeks.

[0156] 5) During screening periods V1 and V2 visits, eGFR ≥ 30 ml / min / 1.73 m 2 (Calculated according to the CKD-EPI 2021 formula);

[0157] 6) During the V1 screening visit (local laboratory testing), the following criteria must be met: ① Hemoglobin ≥ 90 g / L; ② Platelet count ≥ 80 × 10⁻⁶. 9 / L;

[0158] (4) Dosage regimen: Subjects were randomly assigned to four experimental groups, namely 200 mg BID, 300 mg BID, 400 mg BID and placebo, and administered orally twice daily; or subjects were randomly assigned to four experimental groups, namely 100 mg QD, 200 mg QD, 300 mg QD and placebo, and administered orally once daily.

[0159] The present invention has been further described above with reference to specific embodiments. However, it should be understood that the specific description herein should not be construed as limiting the nature and scope of the present invention. Various modifications made to the above embodiments by those skilled in the art after reading this specification are all within the scope of protection of the present invention.

Claims

1. Use of a compound of formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof in the preparation of a medicament for the treatment or prevention of IgA nephropathy or related diseases or conditions, wherein the structure of the compound of formula I is as follows:

2. The use according to claim 1, characterized in that, The intended uses include reducing creatinine and blood urea nitrogen levels in patients with IgA nephropathy; And / or, the use includes reducing proteinuria in patients with IgA nephropathy; And / or, the use includes reducing the urine protein-to-creatinine ratio in patients with IgA nephropathy; And / or, the use includes inhibiting the proliferation of glomerular mesangial cells in patients with IgA nephropathy; And / or, the uses include reducing kidney inflammation and / or fibrosis in patients with IgA nephropathy; And / or, the use includes reducing IgA deposition in the glomeruli of patients with IgA nephropathy; Preferably, the use is in the preparation of a medicament for the treatment or prevention of primary IgA nephropathy or related diseases or conditions.

3. The use according to claim 2, characterized in that, The patient's 24h-UPE ≥ 0.75 g / 24h, or FMV UPCR ≥ 0.8 g / g; and / or, the patient's eGFR ≥ 30 ml / min / 1.73 mcg / min. 2 .

4. The use according to any one of claims 1 to 3, characterized in that, The dosage of the compound of Formula I is 0.1 to 2000 mg / time; preferably 10 to 1000 mg / time; more preferably 50 to 700 mg / time; even more preferably 50 to 500 mg / time; even more preferably 50 to 400 mg / time; and even more preferably 50 mg / time, 100 mg / time, 150 mg / time, 200 mg / time, 250 mg / time, 300 mg / time, 350 mg / time or 400 mg / time.

5. The use according to any one of claims 1 to 4, characterized in that, The dosing frequency of the compound of Formula I is selected from once a day, twice a day, three times a day, once a week, three times a week, once every two weeks, once every three weeks, or once a month; preferably once a day, twice a day, or three times a day; and / or The drug is formulated for oral administration.

6. The use according to any one of claims 1 to 5, characterized in that, Compounds of Formula I can be used alone or in combination with other therapeutic agents or treatments for the treatment or prevention of kidney diseases associated with complement bypass pathway activation.

7. A compound of formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof for the prevention and / or treatment of IgA nephropathy or related diseases or conditions.

8. A pharmaceutical composition for the prevention and / or treatment of IgA nephropathy or related diseases or conditions, characterized in that, The pharmaceutical composition contains a compound of formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof.

9. A pharmaceutical composition for the prevention and / or treatment of IgA nephropathy or related diseases or conditions, characterized in that, The pharmaceutical composition comprises a compound of formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof, and one or more pharmaceutically acceptable carriers.

10. Use of a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof or a hydrate thereof and one or more pharmaceutically acceptable carriers in the preparation of a medicament for the prevention and / or treatment of IgA nephropathy or related diseases or conditions.

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