Crystal of nitrogen-containing bridged heterocyclic compounds and method for preparing the same

Abstract

The present disclosure relates to the crystal of a nitrogen-containing bridged heterocyclic compound and a method for preparing the same. Specifically, the present disclosure relates to a crystalline form of a compound fumarate represented by formula (I). The crystal of the present disclosure has excellent fluidity and can be used more effectively in production and clinical treatment.

Description

Technology Field

[0001] The present disclosure belongs to the field of drug synthesis and relates to the determination of nitrogen-containing bridged heterocyclic compounds and a method for preparing the same. Background Technology

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

[0003] Glomerulopathy includes immunoglobulin A nephropathy (IgA nephropathy, abbreviated as IgAN), C3 glomerulopathy (C3G glomerulopathy, abbreviated as C3G), and membranous glomerulonephritis (MGN). Among these, IgAN and MGN are the most common, while the incidence of rare kidney diseases such as C3 glomerulopathy has also increased over the past decade. Studies have found that glomerulopathy is closely associated with the complement pathway, particularly the complement replacement pathway. Currently, there is a lack of clinically effective treatment options for primary glomerulonephritis. Drug treatment frequently involves the use of drugs such as hormones and immunosuppressants (e.g., cyclophosphamide, mycophenolate mofetil, tacrolimus, cyclosporine A, and the traditional Chinese medicinal plant Tripterygium wilfordii), and other drugs include blood pressure regulating drugs, diuretics and platelet aggregation inhibitors, anticoagulants, lipid-lowering agents, and renal protective and detoxifying drugs such as Cordyceps preparations.

[0004] IgAN is the most common primary glomerular disease worldwide and manifests pathologically as focal glomerular interstitial proliferation, diffuse glomerular interstitial deposition of IgA protein, and substrate increase often accompanied by IgG, C3, and C5b-9 deposition. Therefore, the complement pathway is considered to be involved in the development and progression of IgAN. There are currently two small molecule drugs targeting the complement pathway undergoing clinical trials. OMS721 is a humanized monoclonal antibody targeting the MASP-2 protein, developed by Omeros Inc. The MASP-2 protein is an effector enzyme that activates the lectin pathway of the complement system. At the end of the Phase 2 clinical trial of OMS721, the proteinuria indices of all four participating IgAN patients showed significant improvement. This drug is currently undergoing Phase 3 clinical trials.

[0005] Currently disclosed patent applications for Factor B inhibitors include WO2015009616A1, WO2019043609A1, and WO2020016749A2. WO2022143845 provides a series of nitrogen-containing heterocyclic derivatives, including the compound represented by formula (I), characterizes their structures, and performs biological evaluations; as a result, it was indicated that the compound has a relatively excellent inhibitory effect on Factor B enzyme activity.

[0006]

[0007] The object of the present disclosure is to provide a new nitrogen-containing bridged heterocyclic compound having excellent fluidity, which can be better applied to the manufacture and clinical use of drugs, and a method for preparing the same.

[0008] One aspect of the present disclosure provides a compound fumarate crystal represented by formula (I), the angle of repose θ of which is 45° or less, for example, the angle of repose of which may be 44°, 43°, 42°, 41°, 40°, 39°, 38°, 37°, 36°, 35°, 34°, 33°, 32°, 31° or 30° or less.

[0009] In some embodiments, the Hausner ratio of the crystal is 1.35 or less, for example 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 or less, for example 1 to 1.3.

[0010] In some embodiments, the knife index of the crystal is 26% or less, for example, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, or 15% or less.

[0011] In some embodiments, the crystal is spherical or elliptical.

[0012] In some embodiments, the compound fumarate crystal represented by formula (I) described in the present disclosure has characteristic peaks at 9.6, 14.0, 16.7, 19.6, 25.8, and 26.1 in the X-ray powder diffraction spectrum represented by the diffraction angle 2θ.

[0013] In some embodiments, the fumarate crystal represented by formula (I) described in the present disclosure 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 in the X-ray powder diffraction spectrum represented by the diffraction angle 2θ.

[0014] In some embodiments, the compound fumarate crystal represented by formula (I) described in the present disclosure has 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 in the X-ray powder diffraction spectrum represented by the diffraction angle 2θ.

[0015] In some embodiments, the compound fumarate crystal represented by formula (I) described in the present disclosure has an X-ray powder diffraction spectrum at a diffraction angle 2θ as shown in FIG. 2.

[0016] In some embodiments, the fumarate of the compound represented by formula (I) may be crystalline form I or crystalline form II of the compound fumarate represented by formula (I), for example, crystalline form I.

[0017] In some embodiments, the content (based on weight percentage) of the compound fumarate represented by formula (I) in the compound fumarate crystals represented by formula (I) may be greater than 90%, greater than 92%, greater than 93%, greater than 94%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, or greater than 99%.

[0018] In some embodiments, the present disclosure provides a compound fumarate crystal represented by formula (I), wherein the angle of repose θ is 45° or less, e.g. 35° or less, the Hausner ratio is 1.35 or less, e.g. 1.26 or less, the Carl index is 26% or less, e.g. 21% or less, and the compound fumarate represented by formula (I) is crystalline form I.

[0019] In some embodiments, the content (on a weight percentage basis) of the compound fumarate represented by formula (I) is greater than 95%, for example, greater than 97%.

[0020] Another aspect of the present disclosure provides a method for preparing crystals of a compound fumarate represented by formula (I), the method comprising: mixing a compound fumarate represented by formula (I) with fumaric acid and a solvent under stirring conditions, and precipitating crystals of the compound fumarate represented by formula (I).

[0021] The above solvent may be one or more of C1-C6 alkyl alcohols (e.g., methanol, ethanol, isopropanol, etc.) and acetone.

[0022] In some embodiments, a compound fumarate represented by formula (I) and fumaric acid are first dissolved in solvent A, said solvent A may be a C1-C6 alkyl alcohol, then mixed with solvent B, said solvent B may be acetone, and crystals of the compound fumarate represented by formula (I) are precipitated.

[0023] In some embodiments, a compound fumarate represented by formula (I) and fumaric acid are first dissolved in solvent A, said solvent A may be a C1-C6 alkyl alcohol, the solvent is concentrated, optionally seed crystals are added, then solvent B is added to the system, said solvent B may be acetone, and crystals of the compound fumarate represented by formula (I) are precipitated.

[0024] The reaction temperature of the above method may be 0℃ to 60℃, for example, 0℃ to 40℃.

[0025] The present disclosure further relates to a pharmaceutical composition comprising a compound fumarate crystal represented by formula (I) described in the present disclosure and one or more pharmaceutically acceptable excipients.

[0026] The present disclosure further relates to a pharmaceutical composition prepared by mixing a compound fumarate crystal represented by formula (I) described in the present disclosure with one or more pharmaceutically acceptable excipients.

[0027] The present disclosure further relates to a method for preparing a pharmaceutical composition comprising the step of mixing a compound fumarate crystal represented by formula (I) described in the present disclosure with one or more pharmaceutically acceptable excipients.

[0028] The pharmaceutical compositions described in this disclosure may be prepared in any pharmaceutically acceptable formulation. For example, the crystals or pharmaceutical formulations of this disclosure may be formulated as tablets, capsules, pills, crystals, solutions, suspensions, syrups, injectables (including injectable solutions, sterile powders for injection, and concentrated solutions for injection), suppositories, inhalants, or nebulizers.

[0029] The present disclosure further relates to a raw material pharmaceutical of a compound fumarate represented by formula (I), comprising a compound fumarate crystal represented by formula (I) as described in the present disclosure.

[0030] Based on the total weight of the active pharmaceutical ingredient, the crystal content of the compound fumarate represented by the above formula (I) may be greater than 50%, for example, greater than 70%, greater than 80%, or greater than 90%.

[0031] The present disclosure also provides for the use of a compound fumarate crystal represented by the aforementioned formula (I), an active pharmaceutical ingredient, or the aforementioned composition in the manufacture of a drug for treating a disease or pathology, wherein the disease or pathology is 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 due to Behcet's syndrome, multifocal choroiditis, Vogt-Koyanagi-Harada syndrome, shotn retinochoroiditis, sympathetic ophthalmitis, pituitary pemphigoid, ocular pemphigoid, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, neurological disorders, multiple sclerosis, stroke, Guillain-Barré syndrome, traumatic brain injury, Parkinson's disease, inappropriate or unwanted complement activation disorder, hemodialysis complications, hyperacute Allograft rejection, xenograft rejection, Interleukin-2-induced toxicity during IL-2 therapy, Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemic reperfusion impairment, myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary bypass or renal bypass surgery, atherosclerosis, hemodialysis, renal ischemia, aortic reconstruction, mesenteric artery reperfusion after infectious disease or pyometra, systemic lupus erythematosus, systemic lupus erythematosus nephritis, proliferative glomerulonephritis, 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, fibrosis-inducing dust disease, pulmonary fibrosis, asthma, allergy, bronchoconstriction, parasitic disease, Goodman syndrome, pulmonary vasculitis, minority immune vasculitis, immune complex-related inflammation, Selected from antiphospholipid syndrome and obesity; said disease or condition is preferably C3 glomerulonephropathy, immunoglobulin A nephropathy, membranous glomerulonephritis, atypical hemolytic uremic syndrome and paroxysmal nocturnal hemoglobinuria.

[0032] The fumarate crystals represented by Formula (I) prepared in the present disclosure have excellent fluidity, superior solubility and rapid dissolution rate, high crystal purity, excellent crystal stability under lighting, high temperature, and high humidity conditions, are very stable during manufacturing, storage, and drying processes, and have excellent biocompatibility, which can meet the requirements for the production, transportation, and storage of drugs, and the production process is stable, reproducible, and controllable, making it adaptable for industrial production.

[0033] The structure of the crystal obtained in the present disclosure is measured and the crystal form is studied through X-ray powder diffraction spectrum (XRPD) and differential scanning calorimetry (DSC).

[0034] The starting material used in the crystal manufacturing method of the present disclosure may be a fumarate compound represented by any form of formula (I), and specific forms include, but are not limited to, amorphous, any crystalline, any hydrate or solvate.

[0035] The “X-ray powder diffraction spectrum or XRPD” described in the present disclosure refers to the Bragg formula 2d sinθ=nλ (where λ is the wavelength of the X-ray, λ=1.54056 Å, the diffraction order n is any positive integer, generally taking the first-order diffraction peak, n=1), and when an X-ray is incident on an atomic plane having a lattice plane spacing d of a crystal or partial crystal sample at an index angle θ (complementary angle of the angle of incidence, also called the Bragg angle), the Bragg equation can be satisfied, thereby measuring the X-ray powder diffraction spectrum of this group.

[0036] The "differential scanning calorimetry or DSC" described in this disclosure refers to measuring the temperature difference and heat flux difference between a sample and a reference during a heating or constant temperature process of the sample in order to characterize all physical and chemical changes related to thermal effects and to obtain information on phase changes of the sample.

[0037] "2θ or 2θ angle" described in the present disclosure refers to a diffraction angle, θ is a Bragg angle, the unit is ° or degrees, and the error range of 2θ is ±0.3 or ±0.2 or ±0.1.

[0038] The “crystallial spacing or crystallial spacing (d value)” described in the present disclosure refers to dividing the lattice into parallel parallelepiped units by selecting three non-parallel unit vectors a, b, and c that connect two adjacent lattice points in the spatial lattice, and this is referred to as the crystallial spacing. The spatial lattice is divided according to the determined parallelepiped unit connections to obtain straight lattice lines, which are referred to as the spatial lattice or crystal lattice. The lattice and crystal lattice each use geometric points and lines to reflect the periodicity of the crystal structure, and different crystal planes have different interplanar spacings (i.e., the distance between two adjacent parallel crystal planes); the unit is Å or angstrom.

[0039] The "angle of repose" described in this disclosure refers to the maximum angle measured when a particle is in a stationary state, with the applied gravitational force and the frictional force between the particles in equilibrium, as the particle slides on a free inclined plane of a powder layer within a gravitational field. The angle of repose of the particle is measured using the funnel method, whereby the microparticle material flows out of the funnel and falls onto a flat surface, forming a cone; the base angle of this cone is the angle of repose. The calculation formula is as follows:

[0040]

[0041] Here, h and r are the height and radius of the cone, respectively.

[0042] The "Kal Index" described in this disclosure refers to the Compressibility Index (CI) and is used to evaluate the fluidity of a material. For a material, fluidity decreases as it is compressed more tightly in a tap density test. The Compressibility Index is one of the important indicators of powder fluidity, and its magnitude reflects the agglomeration and looseness of the powder. A certain amount (W) of powder is lightly placed into a graduated cylinder, and the initial volume (V0) is measured. Then, the powder is compressed into a tight state using the tapping method, and the final volume (Vf) is measured. The mass W of the powder is divided by V0 and Vf, respectively, to calculate the minimum bulk density (ρ0) and tap density (ρf). The Compressibility Index CI can be calculated according to the following formula.

[0043]

[0044] The "Hausner Ratio" (HR) described in this disclosure is similar to a compression factor and can be calculated according to the following formula, and the higher the Hausner Ratio, the lower the fluidity.

[0045]

[0046] The relationship between the Carl Index, the Hausner Ratio, and liquidity is shown in the following table.

[0047]

[0048] "Optional" or "optional" means that the event or environment described subsequently may occur but does not necessarily have to occur, and the description includes both cases where the event or environment occurs and cases where it does not occur. For example, "a heterocyclyl group optionally substituted by an alkyl" means that an alkyl may be present but does not necessarily have to be present, and the description includes cases where the heterocyclyl group is substituted by an alkyl and cases where the heterocyclyl group is not substituted by an alkyl.

[0049] The figures in this disclosure have a certain margin of error, and generally, ±10% falls within a reasonable margin of error. Of course, the context in which the figures are used must be considered; for example, in the case of total impurity content, the figure may be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%, such that the change in error after measurement does not exceed ±10%, and preferably ±5%.

[0050] The “pharmaceuticalally acceptable excipients” described in this disclosure include, but are not limited to, all acceptable adjuvants, carriers, fluidizers, sweeteners, diluents, preservatives, dyes / colorants, flavorings, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, or emulsifiers approved by the U.S. Food and Drug Administration for use in humans or livestock animals. Brief explanation of the drawing

[0051] FIG. 1 is the XRPD spectrum of a compound fumarate crystal represented by formula (I) prepared in Example 1; FIG. 2 is the XRPD spectrum of a compound fumarate crystal represented by formula (I) prepared in Example 3; FIG. 3 is a micrograph of a crystal of the compound fumarate represented by formula (I) prepared in Example 1; FIG. 4 is a micrograph of a crystal of the compound fumarate represented by formula (I) prepared in Example 3; FIG. 5 is a scanning electron microscope image of a crystal of the compound fumarate represented by formula (I) prepared in Example 1; Figure 6 is a scanning electron microscope image of a crystal of the compound fumarate represented by formula (I) prepared in Example 3. Specific details for implementing the invention

[0052] The present disclosure will be described in detail below by combining specific examples. Those skilled in the art will fully understand that the specific examples of the present disclosure are merely for illustrating the technical methods of the present disclosure and are not intended to 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: Measurements are performed using a BRUKER D8 X-ray diffractometer, and specific acquisition information is: Cu anode (40 kV, 40 mA), radiation: monochromatic Cu-Ka line (l=1.5418 Å). Scan mode: θ / 2θ, scan 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 stirred to crystallize, and after centrifugation, the solid was vacuum dried to obtain the product.

[0057] By X-ray powder diffraction detection, the product was defined as crystalline fumarate form I, the XRPD spectrum is as shown in Fig. 1, and the position of its characteristic peak is as shown in Table 1. By ion chromatography measurement, the fumarate ion content was 20.34%. Further details regarding the properties of crystalline fumarate form I are described in PCT / CN2023 / 104908, the full contents of which are incorporated into this application.

[0058] Peak position of crystalline form I of fumarate Peak number 2 θ Value [° or degrees] D[Å] Relative strength % 1 4.898 18.02822 7.7 2 6.057 14.58063 31.1 3 9.634 9.17322 72.7 4 10.031 8.81136 62.2 5 10.838 8.15644 36.4 6 12.067 7.32867 5.1 7 13.275 6.66409 10.1 8 14.003 6.31931 51.8 9 14.781 5.98853 8.9 10 16.733 5.29395 62.1 11 17.225 5.14381 55.8 12 18.635 4.75775 40.0 13 19.119 4.63834 59.5 14 19.612 4.52276 76.2 15 20.212 4.38986 33.0 16 21.415 4.14603 5.1 17 21.965 4.04345 20.1 18 22.699 3.91418 24.6 19 24.171 3.67905 10.1 20 24.648 3.60902 6.4 21 25.799 3.45048 100.0 22 26.137 3.40663 93.3 23 26.639 3.34354 18.1 24 27.351 3.25814 7.6 25 28.092 3.17390 5.2 26 29.149 3.06117 9.1 27 30.041 2.97225 10.2 28 31.219 2.86269 4.7 29 31.852 2.80727 1.9 30 32.449 2.75693 1.6 31 34.523 2.59595 4.8 32 35.364 2.53613 10.0 33 36.737 2.44443 3.1 34 37.545 2.39364 2.6 35 39.197 2.29649 2.1 36 40.743 2.21283 2.1 37 41.797 2.15942 4.9 38 43.062 2.09887 5.1

[0059] Example 2

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

[0061] By X-ray powder diffraction detection, the corresponding product was crystalline form I of fumarate.

[0062] Example 3

[0063] Methanol (2100 ml, 6 V), fumaric acid (0.1 eq.), and crystalline form I of the fumarate represented by formula (I) prepared in Example 1 (350 g, 1.0 eq.) were added to a reaction flask, and the temperature was raised to 35°C until completely dissolved. The solvent was concentrated to 3–4 V by filtering while hot, then seed crystals were added, and acetone 10 V was added dropwise in a batch manner while stirring; the temperature was slowly lowered to 5–10°C and stirred to crystallize, filtered, and dried to obtain crystals of the fumaric acid compound represented by formula (I). By X-ray powder diffraction detection, it was crystalline form I of the fumarate, and the XRPD spectrum is as shown in Fig. 2.

[0064] Example 4

[0065] An angle of repose measuring device was constructed in accordance with the provisions of the national standard GB11986-89 regarding "measurement of angle of repose of surfactant powders and particles" (the angle of repose of both powders and particles can be measured by referring to these provisions). Three parallel tests were performed. The angle of repose of the crystals of Example 3 was measured. However, the crystals of Example 1 and Example 2 could not have their angles of repose measured because their fluidity was too low.

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

[0067] item Example 1 Example 3 Crystalline form Determinant I Determinant I Bulk density (g / mL) / 0.548 Tap density (g / mL) / 0.652 Cal Index (%) >32 16 Hausner B. >1.45 1.19 Angle of repose (°) >45 30.6

[0068] The results indicate that the compound fumarate crystals represented by formula (I) prepared in the present disclosure have superior fluidity, making them more advantageous for raw material weighing and formulation preparation. In addition, thanks to the excellent fluidity and spherical appearance of the crystals, they dissolve more quickly, significantly improving production efficiency.

[0069] Example 5. Study on the stability of factors affecting crystalline form I of fumarate

[0070] The crystalline fumarate form I prepared in Example 3 was left flat in an open state, and the stability of the sample was investigated under conditions of illumination (4500 Lux), high temperature (40°C, 60°C), and high humidity (RH 75%, RH 92.5%), respectively, and the sampling investigation period was 30 days.

[0071] condition Time (day) Color, appearance water% Salt type start 0 white solid 100.0 Fumarate crystalline form I Lighting (4500Lux) 5 white solid 100.0 Not converted 10 white solid 99.9 Not converted 30 white solid 99.5 Not converted 40℃ 5 white solid 99.7 Not converted 10 white solid 99.6 Not converted 30 white solid 99.3 Not converted 60℃ 5 white solid 99.8 Not converted 10 white solid 99.7 Not converted 30 white solid 99.5 Not converted 75% RH 5 white solid 100.0 Not converted 10 white solid 99.9 Not converted 30 white solid 100.0 Not converted 92.5% RH 5 white solid 99.9 Not converted 10 white solid 99.9 Not converted 30 white solid 99.9 Not converted

[0072] Conclusion: The physical and chemical stability of crystalline fumarate I is found to be good under conditions of lighting, high temperatures of 40°C and 60°C, and high humidity of 75% and 92.5% for 30 days.

[0073] Example 6. Study on the long-term accelerated stability of crystalline fumarate form I

[0074] The crystalline fumarate form I prepared in Example 3 was sealed and left under conditions of 25°C / 60% RH and 40°C / 75% RH, respectively, to investigate its stability.

[0075] Test conditions Time (Month) water(%) Salt type beginning 100.0 Fumarate crystalline form I 25℃, 60%RH 1 99.9 Not converted 2 100.0 Not converted 3 100.0 Not converted 6 99.9 Not converted 40℃, 75%RH 1 99.9 Not converted 2 99.9 Not converted 3 99.9 Not converted 6 99.8 Not converted

[0076] Conclusion: According to long-term accelerated tests, the physical and chemical stability of crystalline fumarate I is good under conditions of 25℃ / 60% RH and 40℃ / 75% RH for 6 months.

[0077] Since the present disclosure has been described based on specific embodiments, specific variations and equivalent changes will be obvious to those skilled in the art and are also included within the scope of the present disclosure.

Claims

Claim 1 A compound fumarate crystal represented by formula (I), wherein the angle of repose θ is 45° or less, preferably 40° or less, more preferably 35° or less: . Claim 2 In claim 1, the crystal has a Hausner ratio of 1.35 or less, preferably 1.3 or less, more preferably 1 to 1.

3. Claim 3 A crystal according to claim 1 or 2, wherein the cal index of the crystal is 26% or less, preferably 21% or less. Claim 4 In any one of claims 1 to 3, wherein the X-ray powder diffraction spectrum indicated by the 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 spectrum indicated by the diffraction angle 2θ is as shown in FIG. 2, decision. Claim 5 In paragraph 4, the error range of the above 2θ angle is ±0.2, determined. Claim 6 A crystal according to any one of claims 1 to 5, wherein the compound fumarate represented by formula (I) is of crystalline form I. Claim 7 A compound fumarate crystal represented by formula (I), wherein the angle of repose θ is 45° or less, preferably 35° or less, the Hausner ratio is 1.35 or less, preferably 1.26 or less, the Carl index is 26% or less, preferably 21% or less, and preferably the compound fumarate represented by formula (I) is of crystalline form I. Claim 8 A method for preparing a compound fumarate crystal represented by Formula (I) according to any one of claims 1 to 7, comprising the step of mixing the compound fumarate represented by Formula (I) with fumaric acid and a solvent under stirring conditions to precipitate a compound fumarate crystal represented by Formula (I), wherein the solvent may be one or more of C1-C6 alkyl alcohols and acetone. Claim 9 A method according to claim 8, wherein first, a compound fumarate represented by formula (I) and fumaric acid are dissolved in solvent A, said solvent A is a C1-C6 alkyl alcohol, then mixed with solvent B, said solvent B is acetone, and crystals of the compound fumarate represented by formula (I) are precipitated; preferably, first, a compound fumarate represented by formula (I) and fumaric acid are dissolved in solvent A, said solvent A is a C1-C6 alkyl alcohol, the solvent is concentrated, optionally seed crystals are added, then solvent B is added to the system, said solvent B is acetone, and crystals of the compound fumarate represented by formula (I) are precipitated. Claim 10 A method according to claim 8 or 9, wherein the reaction temperature of the method is 0°C to 60°C, preferably 0°C to 40°C. Claim 11 A pharmaceutical composition comprising a compound fumarate crystal represented by formula (I) according to any one of claims 1 to 7 and one or more pharmaceutically acceptable excipients. Claim 12 A pharmaceutical composition prepared by mixing a compound fumarate crystal represented by formula (I) according to any one of claims 1 to 7 with one or more pharmaceutically acceptable excipients. Claim 13 A method for preparing a pharmaceutical composition comprising the step of mixing a compound fumarate crystal represented by formula (I) according to any one of claims 1 to 7 with one or more pharmaceutically acceptable excipients. Claim 14 A raw material pharmaceutical of a compound fumarate represented by Formula (I), comprising a compound fumarate crystal represented by Formula (I) according to any one of Claims 1 to 7. Claim 15 In the manufacture of a drug for treating a disease or pathology, the use of a compound fumarate crystal represented by formula (I) according to any one of claims 1 to 7, a raw material drug according to claim 14, or a pharmaceutical composition according to claim 12 or 13, wherein the disease or pathology 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 due to Behcet's syndrome, multifocal choroiditis, Vogt-Koyanagi-Harada syndrome, shotn retinochoroiditis, sympathetic ophthalmitis, ocular pemphigoid, ocular pemphigoid, non-arteritic ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, neurological disorder, multiple sclerosis, stroke, Guillain-Barré syndrome, traumatic brain injury, Parkinson's disease, impaired inappropriate or unwanted complement activation, hemodialysis complications, hyperacute allograft rejection, xenograft rejection, interleukin-2 toxicity during IL-2 therapy, Crohn's disease, adult respiratory distress syndrome, myocarditis, post-ischemic reperfusion impairment, myocardial infarction, balloon angioplasty, post-pump syndrome in cardiopulmonary bypass or renal bypass surgery, atherosclerosis, hemodialysis, renal ischemia, aortic reconstruction, mesenteric artery reperfusion after infectious disease or pyototoxicosis, systemic lupus erythematosus, systemic lupus erythematous nephritis, proliferative glomerulonephritis, 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, fibrosis-inducing dust disease, pulmonary fibrosis, asthma, allergy, bronchoconstriction, parasitic disease, Goodman syndrome, pulmonary vasculitis, minority immune vasculitis, immune complex-associated inflammation, antiphospholipid syndrome, and obesity; and the above diseases or conditions are more preferably C3 glomerulopathy, immunoglobulin A nephropathy, membranous glomerulonephritis, atypical hemolytic uremic syndrome, and paroxysmal nocturnal hemoglobinuria.

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