Crystals of a nitrogen-containing bridged heterocyclic compound and a method for producing the same

Abstract

This invention relates to a crystal of a nitrogen-bridged heterocyclic compound and a method for its preparation. Specifically, this invention relates to the crystal form of the fumarate salt of the compound shown in formula (I). The crystals of this invention exhibit excellent flowability, making them better suited for production and clinical treatment.

Description

A crystal of nitrogen-bridged heterocyclic compound and preparation method thereof Technical Field

[0001] The present invention belongs to the field of drug synthesis and relates to a crystal of a nitrogen-bridged heterocyclic compound and a preparation method thereof. Background Art

[0002] Complement factor B (Factor B) is a heat-labile β-globulin that is inactivated in 30 minutes at 50°C. It is cleaved by complement factor D into two fragments, Ba and Bb. Bb combines with C3b to form the C3 convertase of the alternative pathway. Complement factor B is a key component of the alternative complement activation pathway and is also known as the C3 activator precursor. Complement factor B has a molecular weight of 93 kDa and a concentration of approximately 3 μM in human blood. It is primarily synthesized in the liver and has also been found in the retinal pigment epithelium.

[0003] Glomerulopathies include immunoglobulin A nephropathy (IgAN), C3 glomerulopathy (C3G glomerulopathy), and membranous glomerulonephritis (MGN). IgAN and MGN are the most common, while the incidence of rare kidney diseases, such as C3 glomerulopathy, has also increased in the past decade. Studies have shown a close association between glomerulopathies and the complement pathway, particularly the alternative complement pathway. Currently, there is a lack of effective clinical treatment options for primary glomerulonephritis. Commonly used medications include steroids and immunosuppressants (such as cyclophosphamide, mycophenolate mofetil, tacrolimus, cyclosporine A, and the traditional Chinese medicine tripterygium wilfordii polyglycosides). Other options include antihypertensive medications, diuretics, antiplatelet agents, anticoagulants, lipid-lowering drugs, and kidney-protecting and detoxifying agents such as cordyceps preparations.

[0004] IgAN is the most common primary glomerular disease worldwide. Its pathological manifestations include focal mesangial proliferation and increased matrix with diffuse mesangial IgA protein deposition, often accompanied by IgG, C3, and C5b-9 deposition. Therefore, the complement pathway is believed to be involved in the development and progression of IgAN. Currently, two small molecule drugs targeting the complement pathway are in clinical trials. OMS721 is a humanized monoclonal antibody developed by Omeros that targets the MASP-2 protein. MASP-2 is the effector enzyme of the lectin pathway that activates the complement system. At the completion of the Phase 2 clinical trial of OMS721, all four participating IgAN patients achieved significant improvement in proteinuria. This drug is currently undergoing Phase 3 clinical trials.

[0005] Patent applications for Factor B inhibitors currently available include WO2015009616A1, WO2019043609A1, and WO2020016749A2. WO2022143845 provides a series of nitrogen-containing heterocyclic derivatives and characterizes their structures. Biological evaluations of the compound represented by formula (I) show that the compound has a strong inhibitory effect on Factor B enzyme activity. Summary of the Invention

[0006] The purpose of the present disclosure is to provide a novel crystal of a nitrogen-bridged heterocyclic compound and a preparation method thereof, wherein the crystal has good fluidity and can be better applied to the preparation and clinical use of drugs.

[0007] On the one hand, the present disclosure provides a crystal of a fumarate salt of a compound represented by formula (I), wherein the angle of repose θ is not greater than 45°, for example, the angle of repose may be not greater than 44°, 43°, 42°, 41°, 40°, 39°, 38°, 37°, 36°, 35°, 34°, 33°, 32°, 31° or 30°.

[0008] In some embodiments, the crystals have a Hausner Ratio of no greater than 1.35, e.g., no greater than 1.34, 1.33, 1.32, 1.31, 1.3, 1.29, 1.28, 1.27, 1.26, 1.25, 1.24, 1.23, 1.22, 1.21, or 1.2, e.g., 1-1.3.

[0009] In some embodiments, the crystals have a Carr Index of no greater than 26%, e.g., no greater than 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, or 15%.

[0010] In some embodiments, the crystals are spherical or ellipsoidal.

[0011] In some embodiments, the fumarate salt crystals of the compound represented by formula (I) described in the present disclosure have an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 9.6, 14.0, 16.7, 19.6, 25.8 and 26.1.

[0012] In some embodiments, the fumarate salt crystals of the compound represented by formula (I) described in the present disclosure have an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, with characteristic peaks at 6.1, 9.6, 10.0, 14.0, 16.7, 17.2, 19.1, 19.6, 25.8 and 26.1.

[0013] In some embodiments, the fumarate salt crystals of the compound represented by formula (I) described in the present disclosure have an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, with characteristic peaks at 6.1, 9.6, 10.0, 10.8, 14.0, 16.7, 17.2, 18.6, 19.1, 19.6, 25.8 and 26.1.

[0014] In some embodiments, the X-ray powder diffraction pattern of the fumarate salt crystals of the compound represented by formula (I) described in the present disclosure expressed in terms of a diffraction angle of 2θ is shown in FIG2 .

[0015] In some embodiments, the fumarate salt of the compound represented by formula (I) can be the crystal form I or crystal form II of the fumarate salt of the compound represented by formula (I), for example, crystal form I.

[0016] In some embodiments, the content of the fumarate salt of the compound represented by formula (I) in the fumarate salt crystals of the compound represented by formula (I) (as a percentage by weight) may be greater than 90%, or greater than 92%, or greater than 93%, or greater than 94%, or greater than 95%, or greater than 96%, or greater than 97%, or greater than 98%, or greater than 99%.

[0017] In some embodiments, the present disclosure provides a fumarate salt crystal of a compound represented by formula (I), wherein the angle of repose θ is not greater than 45°, for example, not greater than 35°, the Hausner ratio is not greater than 1.35, for example, not greater than 1.26, and the Carr index is not greater than 26%, for example, not greater than 21%, and the fumarate salt of the compound represented by formula (I) is crystal form I.

[0018] In some embodiments, the content of the fumarate salt of the compound represented by formula (I) (by weight percentage) is greater than 95%, for example, greater than 97%.

[0019] Another aspect of the present disclosure provides a method for preparing fumarate crystals of the compound represented by formula (I), the method comprising: mixing the fumarate crystal of the compound represented by formula (I) with fumaric acid and a solvent under stirring conditions to precipitate fumarate crystals of the compound represented by formula (I).

[0020] The solvent may be one or more of C1-C6 alkyl alcohol (such as methanol, ethanol, isopropanol, etc.) and acetone.

[0021] In some embodiments, the fumarate salt of the compound represented by formula (I) and fumaric acid are first dissolved in solvent A, which may be a C1-C6 alkyl alcohol, and then mixed with solvent B, which may be acetone, to precipitate crystals of the fumarate salt of the compound represented by formula (I).

[0022] In some embodiments, the fumarate salt of the compound represented by formula (I) and fumaric acid are first dissolved in solvent A, which can be a C1-C6 alkyl alcohol, and the solvent is concentrated, and seed crystals are optionally added. Then, solvent B is added to the system, and solvent B can be acetone, to precipitate fumarate salt crystals of the compound represented by formula (I).

[0023] The reaction temperature of the method can be 0°C-60°C, such as 0°C-40°C.

[0024] The present disclosure further relates to a pharmaceutical composition comprising a fumarate crystal of the compound represented by formula (I) described in the present disclosure, and one or more pharmaceutically acceptable excipients.

[0025] The present disclosure further relates to a pharmaceutical composition, which is prepared by mixing the fumarate crystals of the compound represented by formula (I) described in the present disclosure with one or more pharmaceutically acceptable excipients.

[0026] The present disclosure further relates to a method for preparing a pharmaceutical composition, which comprises mixing the fumarate crystals of the compound represented by formula (I) described in the present disclosure with one or more pharmaceutically acceptable excipients.

[0027] The pharmaceutical compositions of the present disclosure can be prepared into any pharmaceutically acceptable dosage form. For example, the crystals or pharmaceutical preparations of the present disclosure can be formulated into tablets, capsules, pills, crystals, solutions, suspensions, syrups, injections (including injections, sterile powders for injection, and concentrated solutions for injection), suppositories, inhalants, or sprays.

[0028] The present disclosure further relates to a bulk drug of a fumarate salt of the compound represented by formula (I), which comprises the fumarate salt crystals of the compound represented by formula (I) described in the present disclosure.

[0029] Based on the total weight of the bulk drug, the content of the fumarate crystals of the compound represented by formula (I) may be greater than 50%, for example, greater than 70%, or greater than 80%, or greater than 90%.

[0030] The present disclosure also provides the use of the fumarate crystal of the compound represented by the aforementioned formula (I), the raw material drug or the aforementioned composition in the preparation of a drug for treating a disease or condition, wherein the disease or condition is selected from glomerulopathy, 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, Fukuo-Koyanagi-Harada syndrome, birdshot retinochoroiditis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigus, nonarteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, neurological disorders, multiple sclerosis, stroke, Guillain-Barré syndrome, traumatic brain injury, Parkinson's disease, inappropriate or undesirable complement activation disorders, hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2-induced optic neuropathy during IL-2 therapy Toxicity, Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemic reperfusion disorder, myocardial infarction, balloon angioplasty, post-pump syndrome during cardiopulmonary bypass or renal bypass surgery, atherosclerosis, hemodialysis, renal ischemia, aortic reconstruction, mesenteric artery reperfusion after infectious disease or sepsis, systemic lupus erythematosus, systemic lupus erythematosus nephritis, proliferative nephritis, hepatic 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, fibrosing dust disease, pulmonary fibrosis, asthma, allergy, bronchoconstriction, parasitic diseases, Goodman syndrome, pulmonary vasculitis, pauci-immune vasculitis, immune complex-associated inflammation, antiphospholipid syndrome and obesity; the disease or condition is preferably C3 glomerulopathy, immunoglobulin A nephropathy, membranous glomerulonephritis, atypical hemolytic uremic syndrome and paroxysmal nocturnal hemoglobinuria.

[0031] The fumarate crystals of the compound represented by formula (I) prepared in the present invention have good fluidity, good solubility, rapid dissolution, high crystal purity, good crystal stability under conditions of light, high temperature and high humidity, are very stable during the preparation, storage and drying processes, have excellent biocompatibility, can meet the pharmaceutical requirements of production, transportation and storage, and the production process is stable, repeatable and controllable, and can be adapted to industrial production.

[0032] The crystal structure and crystal form of the crystals obtained in the present invention were determined by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC).

[0033] The starting material used in the crystal preparation method of the present invention can be any form of the fumarate of the compound represented by formula (I), including but not limited to: amorphous, any crystal form, any hydrate or solvate, etc.

[0034] The "X-ray powder diffraction pattern or XRPD" in this disclosure refers to the Bragg formula 2d sinθ=nλ (where λ is the wavelength of the X-rays, The diffraction order n is any positive integer, generally the first-order diffraction peak is taken as n=1). When X-rays are incident on an atomic plane with a lattice plane spacing d in a crystal or a part of a crystal sample at a grazing angle θ (the complementary angle of the incident angle, also called the Bragg angle), the Bragg equation is satisfied, thereby measuring this set of X-ray powder diffraction patterns.

[0035] The "differential scanning calorimetry or DSC" mentioned in the present disclosure refers to measuring the temperature difference and heat flow difference between a sample and a reference object during the process of heating or maintaining a constant temperature of the sample to characterize all physical and chemical changes related to thermal effects and obtain phase change information of the sample.

[0036] The “2θ or 2θ angle” mentioned in the present disclosure refers to the diffraction angle, θ is the Bragg angle, the unit is ° or degree, and the error range of 2θ is ±0.3 or ±0.2 or ±0.1.

[0037] The "interplanar spacing or interplanar spacing (d value)" mentioned in the present disclosure refers to the selection of three non-parallel unit vectors a, b, and c connecting two adjacent lattice points in the space lattice. They divide the lattice into juxtaposed parallelepiped units, which are called interplanar spacing. The space lattice is divided according to the determined parallelepiped unit connection lines to obtain a set of straight line grids, which are called space grids or lattices. The lattice and lattice respectively use geometric points and lines to reflect the periodicity of the crystal structure. Different crystal planes have different interplanar spacings (i.e., the distance between two adjacent parallel crystal planes); the unit is Or angstrom.

[0038] The "angle of repose" described in this disclosure refers to the maximum angle measured when a particle is at rest in a gravitational field, when the gravity and friction between particles are balanced while sliding on the free slope of a powder accumulation layer. The angle of repose is determined using the funnel method. The particulate material flows out of the funnel and falls onto a plane, forming a cone. The angle of repose is the angle of the cone base. The calculation formula is:

[0039] Where h and r are the height and radius of the cone, respectively.

[0040] The "Carr's index" described in the present disclosure refers to the compressibility index (CI), which is used to evaluate the fluidity of a material. The tighter the material is compressed in a tap density test, the worse the fluidity. The compression coefficient is one of the important indicators of powder fluidity, and its size reflects the aggregation and looseness of the powder. After a certain amount (W) of powder is gently loaded into a measuring cylinder, the initial volume (V0) is measured, and the powder is compacted by a tapping method, and the final volume (Vf) is measured. The loosest bulk density (ρ0) and tap density (ρf) are calculated by dividing the mass W of the powder by V0 and Vf respectively. The compression coefficient CI can be calculated according to the following formula.

[0041] The "Hausner Ratio" (HR) described in the present disclosure is similar to the compression coefficient and can be calculated according to the following formula. The higher the Hausner Ratio, the worse the fluidity.

[0042] The relationship between the Carr Index, Hausner Ratio and liquidity is shown in the following table.

[0043] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and that the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0044] The numerical values ​​in this disclosure are subject to a certain degree of error. Generally speaking, a value within a reasonable error range of plus or minus 10% is considered. The context in which the value is used must be considered. For example, the total impurity content, which is a value with an error of no more than plus or minus 10% after measurement, may be plus or minus 9%, plus or minus 8%, plus or minus 7%, plus or minus 6%, plus or minus 5%, plus or minus 4%, plus or minus 3%, plus or minus 2%, or plus or minus 1%, preferably plus or minus 5%.

[0045] The "pharmaceutically acceptable excipients" described in this disclosure include, but are not limited to, any adjuvant, carrier, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent or emulsifier approved by the U.S. Food and Drug Administration for use by humans or livestock animals. BRIEF DESCRIPTION OF THE DRAWINGS

[0046] FIG1 is an XRPD pattern of the fumarate crystals of the compound represented by formula (I) prepared in Example 1;

[0047] FIG2 is an XRPD pattern of the fumarate crystals of the compound represented by formula (I) prepared in Example 3;

[0048] FIG3 is a micrograph of the fumarate crystals of the compound represented by formula (I) prepared in Example 1;

[0049] FIG4 is a micrograph of the fumarate crystals of the compound represented by formula (I) prepared in Example 3;

[0050] FIG5 is a scanning electron microscope photograph of the fumarate crystals of the compound represented by formula (I) prepared in Example 1;

[0051] FIG6 is a scanning electron microscope photograph of the fumarate crystals of the compound represented by formula (I) prepared in Example 3. DETAILED DESCRIPTION

[0052] The present disclosure will be explained in detail below with reference to specific examples so that those skilled in the art can have a more comprehensive understanding of the present disclosure. The specific examples are only used to illustrate the technical solutions of the present disclosure and do not limit the present disclosure in any way.

[0053] The compound represented by formula (I) described herein can be prepared according to the method of WO2022143845.

[0054] XRPD is X-ray powder diffraction detection: the measurement is carried out using a BRUKER D8 X-ray diffractometer, specific collection information: Cu anode (40kV, 40mA), radiation: monochromatic Cu-Ka radiation Scanning mode: θ / 2θ, scanning range: 3-48 o .

[0055] Example 1

[0056] About 8 mg of the compound represented by formula (I) and about 2.27 mg of fumaric acid were weighed, 0.2 mL of acetonitrile was added, and the mixture was stirred for crystallization. After centrifugation, the solid was vacuum dried to obtain the product.

[0057] X-ray powder diffraction analysis identified the product as Form I fumarate. The XRPD spectrum is shown in Figure 1, and the locations of its characteristic peaks are shown in Table 1. Ion chromatography analysis revealed a fumarate ion content of 20.34%. Further information regarding the properties of Form I fumarate is described in PCT / CN2023 / 104908, which is incorporated herein by reference in its entirety.

[0058] Table 1 Fumarate I Crystalline Form Peak Position

[0059] Example 2

[0060] About 80 mg of the compound represented by formula (I) was weighed and added to a methanol solution of fumaric acid (0.33 mol / L, 537 μL), and 1.5 mL of acetonitrile was added. The mixture was stirred for crystallization, and the solid was vacuum dried after centrifugation to obtain the product.

[0061] X-ray powder diffraction analysis showed that the product was fumarate I crystalline form.

[0062] Example 3

[0063] Methanol (2100 ml, 6 V), fumaric acid (0.1 eq.), and Form I fumarate of the compound represented by Formula (I) prepared in Example 1 (350 g, 1.0 eq.) were added to a reaction flask and heated to 35°C until dissolved. The solution was filtered while hot and concentrated to 3-4 V. Seed crystals were then added, and 10 V of acetone was added dropwise in portions with stirring. The temperature was slowly lowered to 5-10°C, stirred to crystallize, filtered, and dried to obtain Form I fumarate of the compound represented by Formula (I). X-ray powder diffraction analysis confirmed the fumarate to be Form I, as shown in Figure 2.

[0064] Example 4

[0065] According to the national standard GB11986-89 on "Measurement of the Angle of Repose of Surfactant Powders and Particles" (the angle of repose of both powders and particles can be measured according to this standard), a repose angle measurement device was constructed. Three parallel tests were performed. The angle of repose of the crystals of Example 3 was measured. However, the angle of repose of the crystals of Examples 1 and 2 could not be measured due to their poor fluidity.

[0066] In addition, the Carr index and Hausner ratio of the crystal of Example 3 were measured, as well as the bulk density and tap density of the crystal of Example 3. All the results are shown in Table 2.

[0067] Table 2

[0068] The results show that the fumarate crystals of the compound represented by formula (I) prepared in the present disclosure have better fluidity, which is more convenient for weighing raw materials and preparing formulations. In addition, due to the good fluidity and spherical appearance of the crystals, they dissolve more quickly, greatly improving production efficiency.

[0069] Example 5: Study on the Stability of Factors Affecting Crystal Form I of Fumarate

[0070] The fumarate salt form I prepared in Example 3 was laid open and the stability of the sample was investigated under light (4500 Lux), high temperature (40° C., 60° C.), and high humidity (RH 75%, RH 92.5%) conditions for 30 days.

[0071] Table 3

[0072] Conclusion: The physical and chemical stability of fumarate salt form I was good under light, high temperature of 40℃ and 60℃, and high humidity of 75% and 92.5% for 30 days.

[0073] Example 6 Long-term accelerated stability study of fumarate salt form I

[0074] The fumarate salt form I prepared in Example 3 was sealed and placed under conditions of 25° C. / 60% RH and 40° C. / 75% RH to investigate the stability.

[0075] Table 4

[0076] Conclusion: Long-term accelerated experiments showed that the fumarate salt form I had good physical and chemical stability at 25°C / 60% RH and 40°C / 75% RH for 6 months.

[0077] While the disclosure has been described in terms of specific embodiments thereof, certain modifications and equivalents will be apparent to one skilled in the art and are intended to be included within the scope of the disclosure.

Claims

1. A crystal of the fumarate salt of the compound represented by formula (I), having a repose angle θ of not more than 45°, preferably not more than 40°, more preferably not more than 35° 2. The crystal according to claim 1, wherein the Hausner ratio of the crystal is not greater than 1.35, preferably not greater than 1.3, more preferably 1 - 1.

3.

3. The crystal according to claim 1 or 2, wherein the Carr index of the crystal is not greater than 26%, preferably not greater than 21%.

4. The crystal according to any one of claims 1 - 3, wherein the X - ray powder diffraction pattern expressed in terms of diffraction angle 2θ has characteristic peaks at 9.6, 14.0, 16.7, 19.6, 25.8, and 26.1, preferably has characteristic peaks at 6.1, 9.6, 10.0, 14.0, 16.7, 17.2, 19.1, 19.6, 25.8, and 26.1, more preferably has characteristic peaks at 6.1, 9.6, 10.0, 10.8, 14.0, 16.7, 17.2, 18.6, 19.1, 19.6, 20.2, 25.8, and 26.1, and most preferably the X - ray powder diffraction pattern expressed in terms of diffraction angle 2θ is as shown in Figure 2.

5. The crystal according to claim 4, wherein the error range of the 2θ angle is ±0.

2.

6. The crystal according to any one of claims 1 - 5, wherein the fumarate of the compound represented by formula (I) is in Form I.

7. A fumarate crystal of the compound represented by formula (I), wherein the angle of repose θ is not greater than 45°, preferably not greater than 35°, the Hausner ratio is not greater than 1.35, preferably not greater than 1.26, the Carr index is not greater than 26%, preferably not greater than 21%, and preferably the fumarate of the compound represented by formula (I) is in Form I.

8. A method for preparing the fumarate crystal of the compound represented by formula (I) as described in any one of claims 1-7, which comprises: Under stirring conditions, the fumarate of the compound represented by formula (I) is mixed with fumaric acid and a solvent to precipitate the fumarate crystal of the compound represented by formula (I), wherein the solvent can be one or more of C1 - C6 alkyl alcohols and acetone.

9. According to the method of claim 8, first dissolve the fumarate of the compound represented by formula (I) and fumaric acid in solvent A, wherein solvent A is a C1 - C6 alkyl alcohol, and then mix with solvent B, wherein solvent B is acetone, to precipitate the fumarate crystal of the compound represented by formula (I); preferably first dissolve the fumarate of the compound represented by formula (I) and fumaric acid in solvent A, wherein solvent A is a C1 - C6 alkyl alcohol, concentrate the solvent, optionally add seed crystals, and then add solvent B to the system, wherein solvent B is acetone, to precipitate the fumarate crystal of the compound represented by formula (I).

10. According to the method of claim 8 or 9, wherein the reaction temperature of the method is 0°C - 60°C, preferably 0°C - 40°C.

11. A pharmaceutical composition comprising the fumarate crystal of the compound represented by formula (I) according to any one of claims 1 - 7, and one or more pharmaceutically acceptable excipients.

12. A pharmaceutical composition prepared by mixing the fumarate crystal of the compound represented by formula (I) according to any one of claims 1 - 7 with one or more pharmaceutically acceptable excipients.

13. A method for preparing a pharmaceutical composition, which comprises mixing the fumarate crystal of the compound represented by formula (I) as described in any one of claims 1-7 with one or more pharmaceutically acceptable excipients.

14. A bulk drug of the fumarate of the compound represented by formula (I), which comprises the fumarate crystal of the compound represented by formula (I) as described in any one of claims 1-7.

15. Use of the fumarate crystal of the compound represented by formula (I) as described in any one of claims 1-7, the bulk drug as claimed in claim 14, or the pharmaceutical composition as claimed in claim 12 or 13 in the preparation of a drug for treating a disease or disorder, wherein the disease or disorder is preferably glomerulopathy, 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, Vogt-Koyanagi-Harada syndrome, birdshot retinochoroidopathy, sympathetic ophthalmia, ocular cicatricial pemphigoid, pemphigus ophthalmicus, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, neurological disorder, multiple sclerosis, stroke, Guillain-Barré syndrome, traumatic brain injury, Parkinson's disease, inappropriate or unwanted complement activation disorder, hemodialysis complication, hyperacute allograft rejection, xenograft rejection, interleukin-2-induced toxicity during IL-2 therapy, Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemic reperfusion disorder, myocardial infarction, balloon angioplasty, pump after syndrome in cardiopulmonary artery bypass surgery or renal bypass surgery, atherosclerosis, hemodialysis, renal ischemia, aortic reconstruction, mesenteric artery reperfusion after infectious disease or sepsis, systemic lupus erythematosus, lupus 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 disease, Goodpasture's syndrome, pulmonary vasculitis, pauci-immune vasculitis, immune complex-related inflammation, antiphospholipid syndrome and obesity; the disease or disorder is more preferably C3 glomerulopathy, immunoglobulin A nephropathy, membranous glomerulonephritis, atypical hemolytic uremic syndrome and paroxysmal nocturnal hemoglobinuria.

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