CN-121987632-A - Dosing regimen for nitrogen-containing bridged heterocyclic compounds

CN121987632ACN 121987632 ACN121987632 ACN 121987632ACN-121987632-A

Abstract

The present disclosure relates to dosing regimens for nitrogen-containing bridge heterocyclic compounds. In particular to a method for treating diseases or symptoms, which comprises the step of administering an effective amount of a compound shown as a formula (I) or pharmaceutically acceptable salt thereof to a patient.

Inventors

SHEN KAI
FENG SHENG
SHU CHANG
ZOU YANFANG
ZHANG KAIYUN

Assignees

江苏恒瑞医药股份有限公司

Dates

Publication Date: 20260508
Application Date: 20251031
Priority Date: 20241101

Claims (8)

1. A method of treating a disease or disorder comprising administering to a patient an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day.
2. The method of claim 1, wherein the disease or disorder is a disease or disorder mediated by alternative complement pathway activation, preferably a disease or disorder mediated by Factor B.
3. The method of claim 1, wherein the disease or condition is an inflammatory disorder.
4. A method for treating a disease or disorder, comprising administering to a patient an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once daily, the disease or condition is selected from glomerulopathy, hemolytic uremic syndrome, atypical hemolytic uremic syndrome, paroxysmal sleep hemoglobinuria, age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, uveitis caused by Behcet's syndrome, multifocal choroiditis, focus-willow-original field syndrome, shotgun-like retinochoroiditis, sympathogenic ophthalmitis, ocular cicatricial pemphigoid, ocular pemphigus, non-arteritis ischemic optic neuropathy, post-operative inflammation, retinal vein occlusion, neurological disorders, multiple sclerosis, stroke, guillain-Barre syndrome, traumatic brain injury parkinson's disease, inappropriate or undesired complement activation disorders, hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2 induced toxicity during IL-2 treatment, cloning disease, adult respiratory distress syndrome, myocarditis, post-ischemic reperfusion disorders, myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary bypass surgery or renal bypass surgery, atherosclerosis, hemodialysis, renal ischemia, aortic remodeling, post-infectious disease or sepsis mesenteric artery reperfusion, systemic lupus erythematosus nephritis, proliferative nephritis, liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, acute respiratory distress syndrome, asthma, chronic obstructive pulmonary disease, emphysema, pulmonary embolism and infarction, pneumonia, fibrotic dust disease, pulmonary fibrosis, asthma, allergy, bronchoconstriction, parasitic diseases, goldmann syndrome, pulmonary vasculitis, oligoimmunovasculitis, immune complex-related inflammation, antiphospholipid syndrome, and obesity, preferably C3 glomerulonephropathy, immunoglobulin A nephropathy, membranous glomerulonephritis, atypical hemolytic uremic syndrome, and paroxysmal sleep hemoglobinuria.
5. A method of inhibiting activation of the alternative complement pathway comprising administering to a patient an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day.
6. The method of claim 5, wherein the method of inhibiting activation of the alternative complement pathway is a method of inhibiting Factor B.
7. The method according to any one of claims 1-6, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a dose selected from the group consisting of 10-1500mg, preferably 25mg, 50mg, 75mg, 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 600mg and 800mg.
8. The method according to any one of claims 1-7, wherein the pharmaceutically acceptable salt of the compound of formula (I) is selected from the group consisting of maleate, phosphate, p-toluenesulfonate, sulfate, hydrochloride, fumarate, tartrate, succinate, citrate, malate, methanesulfonate and hydrobromide, preferably fumarate.

Description

Dosing regimen for nitrogen-containing bridged heterocyclic compounds Technical Field The present disclosure pertains to the field of medicine and relates to dosing regimens for nitrogen-containing bridged heterocyclic compounds. Background Complement Factor B (Factor B) is a thermolabile beta globulin that can be inactivated at 50 ℃ for 30 minutes. It can be cleaved by complement factor D into two fragments Ba, bb, which bind to C3b to form the C3 convertase of the alternative pathway. Complement factor B is an important component of the alternative complement pathway, also known as the C3 activator precursor. Complement factor B has a molecular weight of 93kDa and is synthesized in human blood at a concentration of about 3 μm, mainly in the liver, and is also found in ocular retinal pigment epithelial cells. Glomerulopathy (Glomerulopathy) includes immunoglobulin A nephropathy (IgA Nephropathy, igAN for short), C3 glomerulopathy (C3G Glomerulopathy, C3G for short), membranous glomerulonephritis (Membranous Glomerulonephritis, MGN for short), etc. Of these, igAN and MGN are the most common, and rare kidney diseases, such as C3 glomerulopathy, have increased in incidence in recent decades. The glomerulopathy and complement pathways, in particular the alternative complement pathway, were found to be closely related. At present, the primary glomerulonephritis lacks a clinically effective treatment scheme. The medicines for treating common diseases such as hormone and immunosuppressant (such as cyclophosphamide, mycophenolate mofetil, tacrolimus, cyclosporine A, and tripterygium glycosides), and other medicines including blood pressure controlling medicine, diuretic, anti-platelet aggregation medicine, anticoagulant, lipid lowering medicine, cordyceps preparation, etc. IgAN is the most common primary glomerular disease worldwide, and the pathology manifests as local mesangial hyperplasia and matrix augmentation with diffuse mesangial IgA protein deposition, and often with IgG, C3 and C5b-9 deposition. The complement pathway is therefore thought to be involved in the development of IgAN. There are a number of small molecule drugs currently undergoing clinical trials directed to the complement pathway. WO2022143845 provides a series of nitrogen-containing heterocyclic derivatives and structural characterization thereof, wherein the structural characterization comprises biological evaluation of the compound shown in formula (I), and the result shows that the compound has a good inhibition effect on Factor B enzyme activity. WO2024002353 provides a series of pharmaceutically acceptable salts of the compounds of formula (I). Disclosure of Invention The present disclosure provides an improved dosing regimen for nitrogen-containing bridged heterocyclic compounds that improves ease of dosing. In one aspect, the present disclosure provides a method of treating a disease or disorder comprising administering to a patient an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day. In some embodiments, the disease or disorder is a disease or disorder mediated by activation of the alternative complement pathway. In some embodiments, the disease or disorder is a disease or disorder mediated by Factor B. In some embodiments, the disease or condition is an inflammatory disorder. In some embodiments, the disease or disorder is selected from the group consisting of glomerulopathy (e.g., glomerulonephritis), hemolytic uremic syndrome (e.g., escherichia coli-induced hemolytic uremic syndrome), atypical hemolytic uremic syndrome (atypical haemolytic uraemic syndrome, aHUS), paroxysmal sleep hemoglobinuria, age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis (such as anterior uveitis, posterior uveitis and intermediate uveitis), retinitis pigmentosa, macular edema, behcet's syndrome induced uveitis, multifocal choroiditis, foggy-willow-original field syndrome, shotgun-like retinal choroiditis, sympathogenic ophthalmitis, ocular cicatricial pemphigoid, ocular pemphigoid, non-arterial ischemic optic neuropathy, post-operative inflammation, retinal vein occlusion, neurological disorders, multiple sclerosis, stroke, guillain-barre syndrome, traumatic brain injury, parkinson's disease, inappropriate or undesired complement activation disorders, hemodialysis complications, hyperacute allograft rejection, xenograft rejection, IL-2-induced toxicity during treatment, crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemic reperfusion disorders, myocardial infarction, balloon angioplasty, post-operative bypass flow or renal pump, post-operative atherosclerosis, arterial atherosclerosis, inflammatory bowel disease (such as post-operative arterial ischemia, systemic atherosclerosis, autoimmune diseases) or post-inflammatory conditions, autoimmun