Dosing regimen of nitrogen-bridged heterocyclic compounds

Abstract

The present disclosure relates to dosing regimens of nitrogen-bridged heterocyclic compounds. The treatment method comprises the step of administering an effective amount of a compound shown in a formula (I) or a pharmaceutically acceptable salt thereof to a patient.

Description

Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to dosing regimens for nitrogen-bridged heterocyclic compounds. Background Technology

[0002] Complement factor B is a heat-sensitive β-globulin, inactivated at 50°C for 30 minutes. It can be cleaved by complement factor D into two fragments, Ba and Bb. Bb binds to C3b to form the C3 convertase in the alternative pathway. Complement factor B is an important component of the alternative complement activation pathway, also known as a C3 activator precursor. Complement factor B has a molecular weight of 93 kDa, and its concentration in human blood is approximately 3 μM. It is mainly synthesized in the liver, and has also been found synthesized in the retinal pigment epithelial cells of the eye.

[0003] Glomerulopathy includes immunoglobulin A nephropathy (IgAN), C3 glomerulopathy (C3G glomerulopathy, C3G), and membranous glomerulonephritis (MGN). IgAN and MGN are the most common, while the incidence of rare kidney diseases, such as C3 glomerulopathy, has increased in the last decade. Studies have found a close relationship between glomerulopathy and the complement pathway, particularly the alternative complement pathway. Currently, there is a lack of clinically effective treatment options for primary glomerulonephritis. Commonly used drug treatments include hormones and immunosuppressants (such as cyclophosphamide, mycophenolate mofetil, tacrolimus, cyclosporine A, and Tripterygium wilfordii glycosides), as well as other medications such as blood pressure controllers, diuretics, antiplatelet aggregation drugs, anticoagulants, lipid-lowering drugs, and kidney-protecting and detoxifying agents like cordyceps preparations.

[0004] IgAN is the most common primary glomerular disease worldwide, pathologically characterized by localized mesangial proliferation and increased matrix accompanied by diffuse IgA protein deposition in the mesangial area, often with IgG, C3, and C5b-9 deposition. Therefore, the complement pathway is considered to be involved in the development and progression of IgAN. Several small-molecule drugs targeting the complement pathway are currently undergoing clinical trials.

[0005] WO2022143845 provides a series of nitrogen-containing heterocyclic derivatives and provides structural characterization, including the compound shown in formula (I) which underwent biological evaluation, showing that the compound has a good inhibitory effect on Factor B enzyme activity. WO2024002353 provides a series of pharmaceutically acceptable salts of the compounds shown in formula (I).

[0006] Summary of the Invention

[0007] This disclosure provides an improved dosing regimen for nitrogen-bridged heterocyclic compounds that enhances the convenience of administration.

[0008] This disclosure provides a treatment for a disease or symptom, 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.

[0009] In some embodiments, the disease or condition is mediated by activation of the complement bypass pathway. In some embodiments, the disease or condition is mediated by Factor B.

[0010] In some implementations, the disease or condition is an inflammatory disorder.

[0011] In some implementations, the disease or condition is selected from glomerular diseases (such as glomerulonephritis), hemolytic uremic syndromes (such as Escherichia coli-induced hemolytic uremic syndrome), atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria, age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis (such as anterior uveitis, posterior uveitis, and intermediate uveitis), retinitis pigmentosa, macular edema, uveitis caused by Behçet's syndrome, multifocal choroiditis, Fukushima-Koyanagi-Harada syndrome, shotgun retinochoroiditis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigoid, non-arteritis ischemic optic neuropathy, Postoperative inflammation, retinal vein occlusion, neurological disorders, multiple sclerosis, stroke, Gibbs-Barré syndrome, traumatic brain injury, Parkinson's disease, inappropriate or unwanted complement activation disorders, hemodialysis complications, hyperacute allogeneic graft rejection, xenograft rejection, interleukin-2 induced toxicity during IL-2 therapy, Crohn's disease, adult-onset respiratory distress syndrome, myocarditis, ischemia-reperfusion syndrome, myocardial infarction, balloon angioplasty, post-pump complications during cardiopulmonary bypass or renal bypass surgery. Syndrome, atherosclerosis, hemodialysis, renal ischemia, aortic reconstruction, mesenteric artery reperfusion after infectious diseases or sepsis, immune complex disorders, autoimmune diseases (such as rheumatoid arthritis, systemic lupus erythematosus (SLE), immune thrombocytopenic purpura and cold agglutinin syndrome), systemic lupus erythematosus nephritis, proliferative nephritis, liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, acute respiratory distress syndrome (ARDS), asthma Chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia (such as allergic pneumonia), fibrotic dust disease, pulmonary fibrosis, asthma, allergic reactions, bronchoconstriction, parasitic diseases, Goodman's syndrome, pulmonary vasculitis, oligoimmune vasculitis, immune complex-related inflammation, antiphospholipid syndrome, and obesity; wherein, the glomerular disease may be selected from C3 glomerulonephropathy (such as C3 glomerulonephritis), immunoglobulin A nephropathy (such as primary immunoglobulin A nephropathy), and membranous glomerulonephritis.

[0012] In some implementations, the disease is selected from C3 glomerulonephropathy (such as C3 glomerulonephritis), immunoglobulin A nephropathy, membranous glomerulonephritis, atypical hemolytic uremic syndrome, and paroxysmal nocturnal hemoglobinuria.

[0013] This disclosure also provides a method for inhibiting the activation of the complement alternative 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 daily. In some embodiments, the method for inhibiting the activation of the complement alternative pathway is a method for inhibiting Factor B.

[0014] In some embodiments, the dosage of the compound of formula (I) described in this disclosure or a pharmaceutically acceptable salt thereof is selected from 10-1500 mg, for example, it may be 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125mg, 130mg, 140mg, 150mg, 160mg, 170mg, 175mg, 180mg, 190mg, 200mg, 210mg, 220mg, 225mg, 2 30mg, 240mg, 250mg, 260mg, 270mg, 275mg, 280mg, 290mg, 300mg, 310mg, 320mg, 325mg, 330mg, 340 mg, 350mg, 360mg, 370mg, 375mg, 380mg, 390mg, 400mg, 410mg, 420mg, 425mg, 430mg, 440mg, 450m g, 460mg, 470mg, 475mg, 480mg, 490mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 825mg, 850mg, 875mg, 900mg, 925mg, 950mg, 975mg, 1000mg, 1050mg, 1100mg, 1150mg, 1200mg, 1250mg, 1300mg, 1350mg, 1400mg, 1450mg, 1500mg, or any value between any two of these values.

[0015] In some embodiments, the dosage of the compound represented by formula (I) or its pharmaceutically acceptable salt is selected from 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 600 mg and 800 mg, and the frequency of administration is once daily.

[0016] The pharmaceutically acceptable salts of the drugs described in this disclosure may be maleates, phosphates, p-toluenesulfonates, sulfates, hydrochlorides, fumarates, tartrates, succinates, citrates, malates, mesylates, and hydrobromicates, for example, fumarates.

[0017] The routes of administration for the drugs described in this disclosure may include oral administration, parenteral administration, and transdermal administration, wherein parenteral administration includes, but is not limited to, intravenous injection, subcutaneous injection, and intramuscular injection.

[0018] Another aspect of this disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating diseases or conditions, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once daily.

[0019] The term "effective amount" or "therapeutic effective amount" as used in this disclosure includes an amount sufficient to improve or prevent symptoms or conditions of a medical condition. An effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition to be treated, the patient's overall health, the route and dosage of administration, and the severity of side effects. An effective amount may be the maximum dose or administration regimen that avoids significant side effects or toxicity. Detailed Implementation

[0020] Example 1: Safety, tolerability, pharmacokinetic / pharmacodynamic studies of the compound of formula (I) in healthy subjects after single and multiple administrations.

[0021] 1. Test drug

[0022] Tablets of the fumarate of the compound shown in formula (I), in strengths of 25 mg / tablet and 100 mg / tablet;

[0023] Placebo tablets.

[0024] 2. Dosing regimen

[0025] Single-dose escalation trial (SAD):

[0026] This study enrolled healthy adult male and female participants using a single-center, randomized, double-blind, placebo-controlled, single-dose escalation trial design. Six dose groups were pre-designed: 50 mg, 100 mg, 200 mg, and 400 mg. Participants in each dose group were randomly assigned in a 6:2 ratio to receive either the fumarate tablets shown in formula (I) or a placebo, orally once daily. Blood samples were collected from participants in batches to evaluate the safety and pharmacokinetic / pharmacodynamic properties of the drug.

[0027] Multiple-dose escalation trial (MAD)

[0028] This study enrolled healthy adult male and female subjects using a single-center, randomized, double-blind, placebo-controlled, multiple-dose escalation trial design. Multiple dose groups were pre-designed (50 mg QD, 25 mg BID, 50 mg BID, 75 mg BID, 100 mg BID, 200 mg QD, 150 mg BID, 300 mg QD, and 200 mg BID), with 8 healthy adult subjects in each dose group. Participants were randomly assigned in a 6:2 ratio to receive either the fumarate tablets shown in formula (I) or a placebo, with a planned dosing period of 10 days. Blood samples were collected from subjects in batches to evaluate the safety and pharmacokinetic / pharmacodynamic properties of the drug.

[0029] 3. Test Results

[0030] Based on the obtained clinical data from multiple dose groups of the compound of formula (I) in healthy subjects at doses of 50 mg QD, 25 mg BID, 50 mg BID, 75 mg BID, and 100 mg BID, it can be seen that the compound of formula (I) has good safety and tolerability in the subjects.

[0031] Example 2: Efficacy and safety study of the compound shown in formula (I) in treating patients with paroxysmal nocturnal hemoglobinuria.

[0032] 1. Test drug

[0033] Tablets of the fumarate of the compound shown in formula (I) are available in strengths of 10 mg / tablet, 25 mg / tablet, and 100 mg / tablet.

[0034] 2. Inclusion criteria

[0035] 1) Adult subjects, regardless of gender;

[0036] 2) PNH was confirmed by flow cytometry during screening, with granulocyte and monocyte clones ≥10% in size;

[0037] 3) Has not previously received complement inhibitor therapy.

[0038] 3. Dosing regimen

[0039] Tablets of the fumarate of the compound shown in formula (I) are taken orally twice daily (BID) at doses of 50 mg, 75 mg, and 100 mg.

[0040] 4. Test Results

[0041] Based on the obtained clinical data from multiple dose groups of the compound shown in formula (I) at doses of 50 mg BID and 75 mg BID, it can be seen that the effective concentration of the drug can be maintained by oral administration of the compound shown in formula (I) during the administration period.

[0042] 5. Data Analysis

[0043] The PK data collected during the studies in Examples 1 and 2 were further analyzed in the PopPK model.

[0044] The general procedure for developing the PopPK model is summarized as follows:

[0045] 1. Exploratory data analysis;

[0046] 2. Development of basic structural models;

[0047] 3. Assessment of covariate effects;

[0048] 4. Model refinement;

[0049] 5. Model evaluation.

[0050] The final popPK model was used to derive the PK parameters of patients in the group study and to simulate the concentration-time curves of the compound shown in formula (I) of this disclosure in a virtual population.

[0051] The simulation data from the PopPK model are shown in the table below. The results indicate that after a 150 mg QD administration, the Cmax is comparable to that of a 100 mg BID, which has been proven safe in previous examples, and the Ctrough is comparable to that of a 50 mg BID, which has been proven effective. Therefore, the compound shown in formula (I) is suitable for clinical administration via a QD (quantitative dose) method.

[0052] Table 1

[0053]

[0054] Example 3: Safety, tolerability, pharmacokinetic / pharmacodynamic studies of the compound represented by formula (I) in healthy subjects.

[0055] 1. Test drug

[0056] Capsules of the fumarate of the compound shown in formula (I), with a specification of 25 mg / capsule;

[0057] Placebo capsules.

[0058] 2. Dosing regimen

[0059] This study employed a single-center, randomized, double-blind, placebo-controlled trial design, with three pre-set dose groups: 150 mg QD, 400 mg, and 600 mg. The 150 mg QD consisted of 8 subjects taking the compound capsule shown in formula (I) and 4 subjects taking a placebo. The 400 mg and 600 mg dose groups each consisted of 8 subjects taking the compound capsule shown in formula (I) and 2 subjects taking a placebo. The dosing regimen is as follows:

[0060] 1) 150mg QD group: From D1 to D10, subjects took either a capsule of the compound shown in formula (I) or a placebo once daily.

[0061] 2) 400mg and 600mg groups: Subject D1 took either a capsule of the compound shown in formula (I) or a placebo once.

[0062] Blood samples were collected from subjects in batches to evaluate the safety and pharmacokinetic / pharmacodynamic properties of the drug.

Claims

1. A treatment for a disease or symptom comprising administering to a patient an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein, The compound shown in formula (I) or its pharmaceutically acceptable salt is administered once daily.

2. The method according to claim 1, wherein the disease or condition is mediated by activation of the complement bypass pathway, preferably by Factor B.

3. The method according to claim 1, wherein the disease or condition is an inflammatory disorder.

4. A treatment for a disease or symptom, comprising administering to a patient an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein, The compound represented by formula (I) or its pharmaceutically acceptable salt is administered once daily, and the disease or condition is selected from glomerulonephritis, hemolytic uremic syndrome, atypical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria, age-related macular degeneration, geographic atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, uveitis caused by Behçet's syndrome, multifocal choroiditis, Fuku-Koyanagi-Harada syndrome, shotgun retinochoroiditis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigoid, non-arteritis-associated ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, neurological disorders, multiple sclerosis, stroke, Gibbs-Barré syndrome, traumatic brain injury, Parkinson's disease, inappropriate or undesirable complement activation disorder, hemodialysis complications, hyperacute allogeneic graft rejection, xenograft rejection, interleukin-2 induced toxicity during IL-2 treatment, Crohn's disease, adult-onset respiratory distress. Obsessive-compulsive syndrome, myocarditis, ischemia-reperfusion syndrome, myocardial infarction, balloon angioplasty, post-pump syndrome during cardiopulmonary shunt or renal shunt surgery, atherosclerosis, hemodialysis, renal ischemia, aortic reconstruction, mesenteric artery reperfusion after infectious diseases or sepsis, systemic lupus erythematosus, systemic lupus erythematosus nephritis, proliferative glomerulonephritis, liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, acute respiratory distress syndrome. Syndrome, asthma, chronic obstructive pulmonary disease, emphysema, pulmonary embolism and infarction, pneumonia, fibrotic dust disease, pulmonary fibrosis, asthma, allergic reactions, bronchoconstriction, parasitic diseases, Goodman's syndrome, pulmonary vasculitis, oligoimmune vasculitis, immune complex-related inflammation, antiphospholipid syndrome, and obesity; the diseases or conditions mentioned are preferably C3 glomerulonephropathy, immunoglobulin A nephropathy, membranous glomerulonephritis, atypical hemolytic uremic syndrome, and paroxysmal nocturnal hemoglobinuria.

5. A method for inhibiting activation of the alternative complement pathway, comprising administering to a patient an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein, The compound shown in formula (I) or its pharmaceutically acceptable salt is administered once daily.

6. The method according to claim 5, wherein the method for inhibiting complement bypass pathway activation is a method for inhibiting Factor B.

7. The method according to any one of claims 1-6, wherein the dosage of the compound of formula (I) or its pharmaceutically acceptable salt is selected from 10-1500 mg, preferably 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 600 mg and 800 mg.

8. The method according to any one of claims 1-7, wherein the pharmaceutically acceptable salt of the compound represented by formula (I) is selected from maleate, phosphate, p-toluenesulfonate, sulfate, hydrochloride, fumarate, tartrate, succinate, citrate, malate, methanesulfonate and hydrobromide, preferably fumarate.

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