Crystalline form of a hydrochloride salt of a quinoline derivative

Abstract

The present disclosure relates to crystalline forms of trans-4-[1-(3-chloro-phenyl)-7-methoxy-2,4-dioxo-3,4-dihydro-2H-pyrimido[5,4-c]quinolin-3-yl]-cyclohexanecarboxylic acid hydrochloride, methods of preparation, and their use as therapeutic agents for the treatment of inflammatory diseases.

Description

Technical Field

[0001] This disclosure relates to the crystal form of trans-4-[1-(3-chloro-phenyl)-7-methoxy-2,4-dioxo-3,4-dihydro-2H-pyrimidino[5,4-c]quinolin-3-yl]-cyclohexane carbamate, its preparation method, and its use as a therapeutic agent. Background Technology

[0002] Tumor necrosis factor-α (TNF-α), also known as TNF, DIF, TNF-α, TNFA, and TNFSF2, is a cell-associated cytokine that is processed from a 26kDa precursor form into a 17kDa soluble form. TNF-α has been shown to be a primary mediator of inflammation, fever, and acute-phase responses (similar to those observed during acute infection and shock) in humans and animals. Excessive TNF-α has been shown to be lethal. There is now considerable evidence that blocking the effects of TNF-α through the use of soluble TNF receptors or specific neutralizing antibodies is beneficial in various conditions, including autoimmune diseases such as rheumatoid arthritis (RA), non-insulin-dependent diabetes mellitus (NIDDM or type II diabetes), and Crohn's disease.

[0003] Phosphodiesterases (PDEs) comprise a superfamily of enzymes responsible for the hydrolysis and inactivation of the second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Different PDE families (PDE1, PDE2, PDE3, PDE4, etc.) have been identified, exhibiting differences in substrate preference, catalytic activity, sensitivity to endogenous activators and inhibitors, and encoding genes.

[0004] The PDE4 isoenzyme family exhibits a high affinity for cyclic AMP but a weaker affinity for cyclic GMP. Increased cyclic AMP levels induced by PDE4 inhibition are associated with the suppression of widespread inflammatory and immune cell activation, including lymphocytes, macrophages, basophils, neutrophils, and eosinophils. Furthermore, PDE4 inhibition reduces the release of the cytokine TNF-α.

[0005] In view of these physiological effects, a variety of PDE4 inhibitors with different chemical structures have been disclosed for the treatment of chronic and acute inflammatory diseases, as well as other pathological conditions, diseases and disorders known to be easily improved by inhibiting PDE4.

[0006] PDE4 inhibitors are considered useful in the treatment and / or prevention of various diseases / conditions in mammals such as humans, particularly inflammatory and / or allergic diseases, including, for example, asthma, chronic obstructive pulmonary disease (COPD) (e.g., chronic bronchitis and / or emphysema), atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, eosinophilic granuloma, psoriasis, rheumatoid arthritis, septic shock, ulcerative colitis, Crohn's disease, myocardial and cerebral reperfusion injury, chronic glomerulonephritis, endotoxin shock, adult respiratory distress syndrome, multiple sclerosis, cognitive impairment (e.g., in neurological disorders such as Alzheimer's disease), depression, or pain. Ulcerative colitis and / or Crohn's disease are often collectively referred to as inflammatory bowel disease.

[0007] Furthermore, through mechanism-based therapeutic interventions, compounds that inhibit TNF-α production are considered useful for various diseases and disorders. TNF-α inhibitors are considered useful for diseases including, but not limited to, viral, alcoholic, or drug-induced acute and fulminant hepatitis, hepatic steatosis, alcoholic and non-alcoholic, viral and non-viral hepatitis, cirrhosis, autoimmune hepatitis, chronic active hepatitis, Wilson's disease, myasthenia gravis, idiopathic stomatitis, autoimmune inflammatory bowel disease, ulcerative colitis, Crohn's disease, etc. Inflammatory bowel disease, endocrine ophthalmopathy, Graves' disease, sarcoidosis, primary biliary cirrhosis, pancreatitis, nephritis, endotoxic shock, septic shock, hemodynamic shock, sepsis syndrome, ischemia-reperfusion injury, malaria, mycobacterial infection, meningitis, psoriasis, asthma, chronic obstructive pulmonary disease (COPD), eosinophilia, congestive heart failure, fibrotic diseases, cystic fibrosis, pulmonary fibrosis, liver fibrosis, kidney fibrosis, cachexia, graft rejection, transplant rejection, cancer, and diseases involving angiogenesis. Autoimmune diseases, ankylosing spondylitis, autoimmune encephalomyelitis, autoimmune blood disorders, hemolytic anemia, aplastic anemia, pure red cell anemia, idiopathic thrombocytopenic purpura, systemic lupus erythematosus (SLE), polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, Reiter's syndrome, non-infectious uveitis, autoimmune keratitis, keratoconjunctivitis sicca, vernal keratoconjunctivitis, pulmonary interstitial fibrosis, psoriatic arthritis, psoriasis and other benign or malignant proliferative skin diseases, atopic dermatitis, urticaria. Neurodegenerative diseases, Parkinson's disease, Alzheimer's disease, acute and chronic multiple sclerosis, cancer, viral infections (such as SARS, MERS, COVID-19 or human immunodeficiency virus (HIV)), cachexia, thrombosis, inflammatory skin diseases, osteoarthritis (OA), osteoporosis, RA, emphysema, chronic bronchitis, allergic rhinitis, radiation damage, hyperoxia alveolar damage, periodontal disease, non-insulin-dependent diabetes mellitus (type II diabetes) and insulin-dependent diabetes mellitus (juvenile or type I diabetes).

[0008] Due to their unique mechanism of action, PDE4 inhibitors may be a valuable treatment option for respiratory viral infections such as SARS, MERS, or COVID-19, as they inhibit upstream pathways of multiple cytokine signaling pathways while regulating the pro-inflammatory / anti-inflammatory balance. Furthermore, PDE4 inhibitors may specifically improve airway and lung inflammation and protect patients from associated acute lung injury and severe respiratory failure, which can lead to intubation and high mortality.

[0009] Therefore, there is a continued need to identify and develop novel compounds that inhibit PDE4 enzyme activity and / or TNF-α production. Summary of the Invention

[0010] As used herein, compound I refers to

[0011]

[0012] The compound can be identified as trans-4-[1-(3-chloro-phenyl)-7-methoxy-2,4-dioxo-3,4-dihydro-2H-pyrimidino[5,4-c]quinolin-3-yl]-cyclohexane carboxylate salt.

[0013] This document describes the crystal forms of compound I, their preparation, pharmaceutical compositions comprising the crystal forms of compound I, and their use as a PDE4 activity inhibitor and in the treatment of various medical conditions. In some aspects, this disclosure provides polymorphic forms of compound I (“Form I”).

[0014] These and other embodiments of the present invention will be described in more detail in the following detailed description. Attached Figure Description

[0015] Figure 1 This is an X-ray powder diffraction ("XRPD") pattern of Form I.

[0016] Figure 2 It is a differential scanning calorimetry (DSC) curve of form I.

[0017] Figure 3 It is a thermogravimetric analysis of form I (“TGA”).

[0018] Figure 4 It is a solid of form I 13 C NMR spectroscopy.

[0019] Figure 5 It is the Fourier transform infrared ("FT-IR") spectrum of form I. Detailed Implementation

[0020] definition

[0021] Unless otherwise stated, the structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, in addition to replacing hydrogen atoms with deuterium or tritium, or using isotopically enriched atoms... 13 C or 14 Compounds having this structure, except those in which carbon atoms are replaced by carbon atoms in C, are within the scope of this invention.

[0022] The term "therapeuticly effective amount" is used herein to refer to the amount of compound I that will elicit a therapeutic response in the target subject. In one embodiment, the therapeutic response may be inhibition of PDE4 enzyme activity and / or inhibition of TNF-α production in individual cells, tissues, or organs of the subject. In one embodiment, a therapeutically effective amount may be achieved in the subject by administering a dose of less than 1 gram or less than 100 mg of the compound daily. In another embodiment, the daily dose level is greater than 1 mg of the compound. In one embodiment, the dose of compound I administered is 1 to 100 mg, or 1 to 50 mg, or 10 to 50 mg, or 30 to 50 mg. In other embodiments, the dose of compound I administered is 1 to 20 mg, or 5 to 15 mg, or 10 to 20 mg, or 20 to 30 mg.

[0023] As used herein, the term “treatment” refers to comprehensive care for a given condition or disorder that a subject is suffering from, including relief or improvement of one or more symptoms caused by the disorder, in order to delay the onset or progression of the disorder.

[0024] The term "object" can refer to any mammal, such as, but not limited to, humans. In one embodiment, the object is a human being. In another embodiment, the object is a human being exhibiting one or more symptom characteristics of a condition to be treated. The term "object" does not require the object to have any specific identity in relation to any hospital, clinic, or research institution (e.g., as an inpatient, research participant, etc.). In one embodiment, the object can be an "object in need."

[0025] A “pharmaceutically acceptable carrier” is a medium generally accepted in the art for delivering a bioactive agent to a mammal (e.g., a human). Such a carrier is typically formulated based on a range of factors that can be determined and interpreted by one of ordinary skill in the art. These factors include, but are not limited to: the type and nature of the active agent being formulated; the target of the pharmaceutical composition; the intended route of administration of the composition; and the intended therapeutic indication. Pharmaceutically acceptable carriers include aqueous and non-aqueous liquid media, as well as various solid and semi-solid dosage forms. In addition to the active agent, such a carrier may also include several different components and additives, which are included in the formulation for various reasons (e.g., stabilization of the active agent, as is well known to one of ordinary skill in the art). Descriptions of suitable pharmaceutically acceptable carriers, and the factors involved in their selection, can be found in various readily available sources, such as Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa. 1985, the contents of which are incorporated herein by reference.

[0026] The term "pharmaceutically acceptable salt" refers to a salt prepared from pharmaceutically acceptable inorganic and organic acids, and inorganic and organic bases. For example, compound I can react with many inorganic and organic acids to form pharmaceutically acceptable acid addition salts, such as, but not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, propionic acid, citric acid, tartaric acid, and benzoic acid. Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, for example, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to: primary amine salts, secondary amine salts, and tertiary amine salts. Specific examples of these amines include, for instance, isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, and ethylenediamine. These pharmaceutically acceptable salts and common methods for their preparation are well known in the art. See, for example, P. Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection and Use, (VCHA / Wiley-VCH, 2002); SMBerge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Sciences, Vol. 66, No. 1, January 1977.

[0027] Crystal form of compound I

[0028] Implementation Scheme 1 (E1). The present invention provides the crystal form of trans-4-[1-(3-chloro-phenyl)-7-methoxy-2,4-dioxo-3,4-dihydro-2H-pyrimidino[5,4-c]quinolin-3-yl]-cyclohexane carbamate.

[0029] E2. The crystal form according to E1, characterized in that, measured using Cu Kα X-rays, the XRPD spectrum has peaks at 2θ angles of 11.6°±0.2°, 12.0°±0.2° and 24.1°±0.2°.

[0030] E3. The crystal form according to E1 or E2, characterized in that, measured using Cu Kα X-rays, the XRPD spectrum has peaks at 2θ angles of 11.6°±0.2°, 12.0°±0.2°, 14.2°±0.2° and 24.1°±0.2°.

[0031] E4. The crystal form according to any one of E1 to E3, characterized in that the XRPD pattern is substantially as follows: Figure 1As shown, or the peak values ​​are shown in Table 1.

[0032] E5. The crystal form according to any one of E1 to E4, characterized in that the first endothermic peak begins at about 231°C and the second endothermic peak begins at about 354°C, or characterized in that the first endothermic peak has a peak at about 263°C and the second endothermic peak has a peak at about 360°C, as determined by DSC.

[0033] E6. The crystal form according to any one of E1 to E5, characterized in that the DSC curve is substantially as follows: Figure 2 As shown.

[0034] E7. The crystal form according to any one of E1 to E6, characterized in that, from about 25°C to about 127°C, the weight loss is about 0.8% wt / wt, from about 130°C to about 300°C, the weight loss is about 6.9% wt / wt, from about 300°C to about 350°C, the weight loss is about 1.7% wt / wt, and / or from about 25°C to about 350°C, the weight loss is about 9.5%, as determined by the TGA.

[0035] E8. The crystal form according to any one of E1 to E7, characterized in that the TGA curve is substantially as follows: Figure 3 As shown.

[0036] E9. The crystal form according to any one of E1 to E8, characterized in that, when the external reference value of the carbonyl resonance of glycine is 176.5 ppm, the solid state... 13 The C NMR spectrum has a peak at one of the following locations: 177.4, 161.9, 149.4, or 130.7 ppm.

[0037] E10. The crystal form according to any one of E1 to E9, characterized in that, when the external reference value of the carbonyl resonance of glycine is 176.5 ppm, the solid state... 13 The C NMR spectrum shows peaks at 177.4, 161.9, 149.4 and 130.7 ppm.

[0038] E11. The crystal form according to any one of E1 to E10, characterized in that, when the external reference value of the carbonyl resonance of glycine is 176.5 ppm, the solid state... 13 The C NMR spectrum shows peaks at 177.4, 161.9, 149.4, 139.3, 130.7, 118.0, 117.4 and 108.6 ppm.

[0039] E12. The crystal form according to any one of E1 to E11, characterized in that the solid state... 13 CNMR spectra are basically as follows Figure 4 As shown.

[0040] E13. The crystal form according to any one of E1 to E12, characterized in that at 1679 and 1731 cm⁻¹ -1 At this point, an FT-IR peak appears.

[0041] E14. The crystal form according to any one of E1 to E13, characterized in that at 768, 1447, 1626, 1679, 1731 and 1742 cm⁻¹ -1 At this point, an FT-IR peak appears.

[0042] E15. The crystal form according to any one of E1 to E14, characterized in that the FT-IR peaks are substantially as follows: Figure 5 As shown.

[0043] E16. The crystal form according to any one of E1 to E15, characterized in that the crystal form has at least two or at least three of the following features (a) to (e):

[0044] a) The XRPD spectrum obtained by Cu Kα X-ray measurement has peaks at 2θ angles of 11.6°±0.2°, 12.0°±0.2° and 24.1°±0.2°;

[0045] b) The DSC curve is basically as follows: Figure 2 As shown;

[0046] c) The TGA curve is basically as follows Figure 3 As shown;

[0047] d) When the external reference value for the carbonyl resonance of glycine is 176.5 ppm, the solid state... 13 The CNMR spectrum shows peaks at 177.4, 161.9, 149.4 and 130.7 ppm;

[0048] e) at 1679 and 1731 cm -1 At this point, an FT-IR peak appears.

[0049] E17. The crystal form according to any one of E1 to E16, characterized in that the unit cell is indexed to the original monoclinic.

[0050] E18. The crystal form according to any one of E1 to E17, characterized in that the a value of the unit cell is approximately The value of b is approximately And the value of c is approximately

[0051] E19. The crystal form according to any one of E1 to E18, characterized in that the volume of the unit cell is approximately

[0052] E20. The crystal form according to any one of E1 to E19, characterized in that, in the particle size distribution, the D10 value is about 10 μm to about 25 μm, the D50 value is about 35 μm to about 50 μm, and / or the D90 value is about 85 μm to about 100 μm.

[0053] E21. The crystal form according to any one of E1 to E20, wherein the crystal form is substantially free of other polymorphic forms.

[0054] E22. The crystal form according to any one of E1 to E21, wherein the polymorphic purity of said crystal form is at least about 80%, or at least about 90%, or at least about 95%, or at least about 99%.

[0055] Method for producing crystal form I

[0056] In another aspect, the present invention provides a method for producing a crystal form according to any one of embodiments 1 to 22, the method comprising:

[0057] a) Mix trans-4-[1-(3-chloro-phenyl)-7-methoxy-2,4-dioxo-3,4-dihydro-2H-pyrimidino[5,4-c]quinolin-3-yl]-cyclohexanecarboxylic acid or a salt thereof in an aqueous solution containing hydrochloric acid, wherein the aqueous solution is at least 30°C;

[0058] b) Cool the mixture to below 30°C.

[0059] The aqueous solution containing hydrochloric acid may include 6M HCl, or may be a 6M HCl solution. Steps a) and b) may be repeated once, twice, three times, or more before collecting or filtering the solids in the solution. The aqueous solution in step a) may be at least 50°C, or at least 55°C, or at least 60°C. The mixing in step a) may continue for at least 10 minutes, 15 minutes, 30 minutes, or more than 60 minutes before cooling the mixture. The mixture in step b) may be cooled to below 25°C or below 20°C for at least 5 minutes, 10 minutes, or 15 minutes before repeating step a) or before collecting or filtering the solids in the solution. In step a), a pharmaceutically acceptable salt of trans-4-[1-(3-chloro-phenyl)-7-methoxy-2,4-dioxo-3,4-dihydro-2H-pyrimidino[5,4-c]quinoline-3-yl]cyclohexanecarboxylic acid may be used as a starting material. The pharmaceutically acceptable salt may be a hydrochloride salt.

[0060] In another aspect, the present invention provides a method for producing a crystal form according to any one of embodiments 1 to 22, the method comprising:

[0061] a) Hydrolyzing the ester group of trans-4-[1-(3-chlorophenyl)-7-methoxy-2,4-dioxo-pyrimido[5,4-c]quinolin-3-yl]cyclohexanecarboxylic acid in acidic solution to produce trans-4-[1-(3-chlorophenyl)-7-methoxy-2,4-dioxo-3,4-dihydro-2H-pyrimido[5,4-c]quinolin-3-yl]cyclohexanecarboxylic acid or a salt thereof; and

[0062] b) Add water to the acidic solution to form a precipitate.

[0063] In one embodiment, the acidic solution in step a) may include acetic acid and hydrochloric acid. In another embodiment, the acidic solution is a mixture of acetic acid and 6M HCl. In another embodiment, the acidic solution in step a) may be maintained below 30°C or between 20 and 30°C during hydrolysis. In a further embodiment, the method may include the additional step of: c) separating the precipitate from the acidic solution. In a further embodiment, the method may include the additional step of: d) washing the precipitate with a hydrochloric acid solution, such as 5M HCl or 6M HCl. In a further embodiment, the method may include the additional step of: e) slurrying the precipitate in the hydrochloric acid solution and heating the solution to at least 50°C, or at least 55°C, or at least 60°C. Step e) may be continued for at least 5 minutes, 10 minutes, or 15 minutes, and then, before repeating this step or before collecting the precipitate in the solution, the slurry is cooled to below 30°C or below 25°C and maintained for at least 5 minutes, 10 minutes, or 15 minutes.

[0064] Pharmaceutical Composition

[0065] In another aspect, the present invention provides a pharmaceutical composition comprising a crystal form of compound I and a pharmaceutically acceptable carrier. In one embodiment, the present invention provides a pharmaceutical composition comprising a crystal form of compound I according to any one of embodiments E1 to E22.

[0066] In another embodiment, the present invention provides a pharmaceutical composition according to any one of the foregoing embodiments, and said pharmaceutical composition further comprises one or more additional therapeutic agents. The one or more additional therapeutic agents are selected from steroidal compounds, cyclooxygenase inhibitors, nonsteroidal anti-inflammatory drugs, or TNF-α antibodies, for example, acetylsalicylic acid, buprofen, diclofenac potassium, sulindac, diclofenac sodium, ketoroxyprogesterone acetate, tometetin, ibuprofen, naproxen, naproxen sodium, tiprofenicol, flurbiprofen, mefenamic acid, fluniformic acid, meclofenamic acid, indomethacin, proglumetacine, ketoprofen, nabumetone, acetaminophen, piroxicam, tenofovir. Oxicam, Nimesulide, Phenythagorean, Tramadol, Beclomethasone Dipropionate, Betamethasone, Beclomethasone, Budesonide, Fluticasone, Mometasone, Dexamethasone, Hydrocortisone, Methylprednisolone, Prednisolone, Prednisolone, Triamcinolone, Celecoxib, Rofecoxib, Infliximab, Leflunomide, Etanercept, Methotrexate, Sulfasalazine, Anti-lymphocyte Immunoglobulin, Anti-thymocyte Immunoglobulin, Azathioprine, Cyclosporine, Tacrolimus, Asomycin, Rapamycin, or Moromumab-CD3.

[0067] The present invention further provides a pharmaceutical composition according to any one of the foregoing embodiments, said pharmaceutical composition comprising a therapeutically effective amount of compound I.

[0068] According to another aspect of the invention, a method for preparing a pharmaceutical composition is also provided, the method comprising: mixing a crystal form of compound I with one or more pharmaceutically acceptable carriers.

[0069] Pharmaceutical compositions can exist in unit dose form, each unit dose containing a predetermined amount of the active ingredient. As a non-limiting example, such a unit may contain 0.5 mg to 1 g of compound I, depending on the condition being treated, the route of administration, and the patient's age, weight, and condition. Typical unit dose formulations are those containing a daily dose or sub-dose, or an appropriate fraction thereof, of the active ingredient as described herein. Such pharmaceutical compositions can be prepared by any method well known in the pharmaceutical field.

[0070] In one embodiment, the individual dosage form of the pharmaceutical composition may include a crystal form of compound I in a concentration greater than 1 mg. In another embodiment, the pharmaceutical composition may include a crystal form of compound I in a concentration of 1 to 100 mg, or 1 to 50 mg, or 10 to 50 mg, or 30 to 50 mg. In other embodiments, the pharmaceutical composition may include a crystal form of compound I in a concentration of 1 to 20 mg, or 5 to 15 mg, or 10 to 20 mg, or 20 to 30 mg.

[0071] Pharmaceutical compositions are suitable for any appropriate route of administration, such as oral administration (including sublingual or sublingual), rectal administration, nasal administration, topical administration (including sublingual, sublingual, or transdermal administration), vaginal administration, or parenteral administration (including subcutaneous, intramuscular, intravenous, or intradermal administration). These formulations can be prepared by any method known in the pharmaceutical field, for example, by associating the active ingredient with a carrier or excipient. For example, without limiting the invention, certain routes may be more suitable than others for certain conditions and disorders that may be useful for Compound I.

[0072] Pharmaceutical compositions suitable for oral administration can exist as discrete units, such as capsules or tablets; powders or granules; solutions or suspensions, each containing an aqueous or non-aqueous liquid; edible foams or agitators; or oil-in-water or water-in-oil liquid emulsions. For example, for oral administration in tablet or capsule form, the active pharmaceutical ingredient can be combined with an orally administered, non-toxic, pharmaceutically acceptable inert carrier, such as ethanol, glycerol, or water. Typically, powders are prepared by pulverizing the compound to a suitable fine size and mixing it with a suitable pharmaceutical carrier, such as an edible carbohydrate, for example, starch or mannitol. Flavoring agents, preservatives, dispersants, and colorants may also be present.

[0073] Capsules are made by preparing a mixture of powder, liquid, or suspension and encapsulating it with gelatin or other suitable shell materials. Before encapsulation, glidants and lubricants, such as silica sol, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol, may be added to the mixture. Disintegrants or solubilizers, such as agar, calcium carbonate, or sodium carbonate, may also be added to improve the effectiveness of the medication when ingested. Furthermore, suitable binders, lubricants, disintegrants, and colorants may be incorporated into the mixture when needed or necessary. Examples of suitable binders include starch, gelatin, natural sugars (such as glucose or β-lactose), corn sweeteners, natural and synthetic gums (such as gum arabic, xanthocyanin, or sodium alginate), carboxymethyl cellulose, polyethylene glycol, paraffin wax, etc.

[0074] Useful lubricants in these formulations include, for example, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, and sodium chloride. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, and xanthan gum.

[0075] Tablets are formulated, for example, by preparing a powder mixture, granulation or impaction, adding lubricants and disintegrants, and compression into tablets. The powder mixture can be prepared by mixing a suitably pulverized compound with a diluent or matrix as described above. Optional components include binders (such as carboxymethyl cellulose, alginate, gelatin, or polyvinylpyrrolidone), solution retardants (such as paraffin), reabsorption promoters (such as quaternary ammonium salts), and / or absorbents (such as bentonite, kaolin, or dicalcium phosphate). The powder mixture can be wet-granulated using binders such as syrups, starch pastes, acadia mucilage, or solutions of cellulose or polymeric materials, and then force-sieved. As an alternative to granulation, the powder mixture can be compressed using a tableting machine, resulting in the incompletely formed lumps being broken into granules. The granules can be lubricated by adding stearic acid, stearates, talc, or mineral oil to prevent them from sticking to the tablet forming die. The lubricated mixture is then compressed into tablets. Compound I can also be combined with a free-flowing inert carrier and directly compressed into tablets without the granulation or impaction step. Transparent or opaque protective coatings are available, consisting of a shellac-sealed coating layer, a sugar or polymer material coating layer, and a paraffin-polished coating layer. Dyes can be added to these coatings to differentiate different unit doses.

[0076] Where appropriate, oral dosage units can be microencapsulated. Formulations can also be prepared, for example, by coating or embedding particulate materials in polymers, paraffin, etc., to prolong or maintain release.

[0077] Oral liquids, such as solutions, syrups, and elixirs, can be prepared in unit dosage forms so that a given amount of oral liquid contains a predetermined amount of compound. Syrups can be prepared, for example, by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared using a non-toxic alcoholic solvent. Suspensions are generally formulated by dispersing the compound in a non-toxic solvent. Solubilizers and emulsifiers, such as ethoxylated isostearyl alcohol and sorbitol polyoxyethylene ether; preservatives; flavoring additives, such as peppermint oil; or natural sweeteners, such as saccharin; or other artificial sweeteners may also be added.

[0078] Pharmaceutical compositions suitable for topical administration can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils.

[0079] For the treatment of the eyes or other external tissues, such as the mouth and skin, these formulations can be applied as topical ointments or creams. When formulating ointments, the active ingredient can be used with paraffin or a water-soluble ointment base. Alternatively, the active ingredient can be formulated into a cream with an oil-in-water or water-in-oil base. Pharmaceutical compositions suitable for topical application to the eyes include eye drops in which the active ingredient is suspended in a suitable carrier, particularly an aqueous solvent.

[0080] Pharmaceutical compositions suitable for topical application in the oral cavity include lozenges, candy lozenges, and mouthwashes.

[0081] Pharmaceutical compositions in which the carrier is solid and suitable for nasal administration include coarse powders. These powders are administered by nasal inhalation, i.e., by rapid inhalation through the nasal passage from a container containing the powder near the nose. Suitable formulations in which the carrier is liquid and suitable for administration as nasal sprays or drops include aqueous or oil solutions of the active ingredient.

[0082] Drug compositions suitable for inhalation administration include fine particulate dust or mist, which can be generated by various types of metered pressurized nebulizers, atomizers, or blowers.

[0083] In another aspect, the present invention provides a method for manufacturing a pharmaceutical composition comprising the crystal form of compound I according to any one of embodiments E1 to E22.

[0084] Treatment

[0085] In another aspect, the present invention provides a treatment method comprising: administering to a subject in need a crystalline form of compound I, or administering a pharmaceutical composition comprising a crystalline form of compound I and a pharmaceutically acceptable carrier. In one embodiment, the method comprises: administering a therapeutically effective amount of compound I. In another embodiment, the treatment method comprises: administering to a subject in need a crystalline form of compound I according to any one of embodiments E1 to E22, or administering to a subject in need a pharmaceutical composition comprising a crystalline form of compound I according to any one of embodiments E1 to E22 and a pharmaceutically acceptable carrier.

[0086] The pharmaceutical compositions of the present invention can be administered at a dose level of less than 1 g of compound I per dose or daily. In another embodiment, the dose level administered per dose or daily is greater than 1 mg of compound I. The amount of active ingredient that can be combined with a carrier material to produce a single dose varies depending on the host being treated and the specific route of administration. For example, in a non-limiting embodiment, a unit dosage form for oral administration to humans, such as a tablet or capsule, may contain less than 100 mg of compound I with a suitable and convenient amount of carrier material. In another embodiment, the daily dose level is greater than 1 mg of compound I. In one embodiment, the dose of compound I administered is 1 to 100 mg, or 1 to 50 mg, or 10 to 50 mg, or 30 to 50 mg. In other embodiments, the dose of compound I administered is 1 to 20 mg, or 5 to 15 mg, or 10 to 20 mg, or 20 to 30 mg.

[0087] The daily (once daily, twice daily, etc.) or cycle (once weekly, twice weekly, etc.) dosage and / or frequency can be individualized by the clinician based on the specific clinical symptoms of the patient being treated. Therefore, it is understood that the specific dosage level and frequency of administration for any particular patient can depend on a variety of factors, such as, but not limited to, age, weight, general health condition, sex, diet, time of administration, route of administration, excretion rate, drug combination, and the severity of the specific disease being treated.

[0088] Another embodiment of the present invention includes a method for inhibiting TNF-α activity in a desired subject by administering compound I.

[0089] Another embodiment of the present invention includes a method for inhibiting PDE4 in a desired object by applying compound I.

[0090] Another embodiment of the invention includes a method for treating a condition or disorder mediated by TNF-α activity by administering compound I.

[0091] Another embodiment of the invention includes a method for treating a condition or disorder mediated by PDE4 by administering compound I.

[0092] Another embodiment of the invention includes a method of treating an inflammatory disease by administering compound I. As a non-limiting example, inflammatory diseases may include viral, alcoholic, or drug-induced acute and fulminant hepatitis, hepatic steatosis, alcoholic and non-alcoholic, viral and non-viral hepatitis, cirrhosis, autoimmune hepatitis, chronic active hepatitis, Wilson's disease, myasthenia gravis, idiopathic stomatitis diarrhea, autoimmune inflammatory bowel disease, ulcerative colitis, Crohn's disease, inflammatory bowel disease, endocrine ophthalmopathy, Graves' disease, sarcoidosis, primary biliary cirrhosis, pancreatitis, nephritis, and endotoxins. Shock, septic shock, hemodynamic shock, sepsis syndrome, ischemia-reperfusion injury, malaria, mycobacterial infection, meningitis, psoriasis, asthma, chronic obstructive pulmonary disease (COPD), eosinophilia, congestive heart failure, fibrotic diseases, cystic fibrosis, pulmonary fibrosis, liver fibrosis, kidney fibrosis, cachexia, graft rejection, graft-versus-host disease, transplant rejection reaction, cancer, diseases involving angiogenesis, autoimmune diseases, ankylosing spondylitis, autoimmune encephalopathy Myelitis, autoimmune blood disorders, hemolytic anemia, aplastic anemia, pure red cell anemia, idiopathic thrombocytopenic purpura, systemic lupus erythematosus (SLE), polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, Reiter's syndrome, non-infectious uveitis, autoimmune keratitis, keratoconjunctivitis sicca, vernal keratoconjunctivitis, pulmonary interstitial fibrosis, psoriatic arthritis, psoriasis and other benign or malignant proliferative skin diseases, atopic dermatitis, urticaria, neurodegenerative diseases, Parkinson's disease. Morpheus disease, Alzheimer's disease, acute and chronic multiple sclerosis, cancer, viral infections (such as SARS, MERS, COVID-19 or human immunodeficiency virus (HIV)), cachexia, thrombosis, inflammatory skin diseases, osteoarthritis (OA), osteoporosis, RA, emphysema, chronic bronchitis, allergic rhinitis, radiation damage, hyperoxia alveolar damage, periodontal disease, non-insulin-dependent diabetes mellitus (type II diabetes) and insulin-dependent diabetes mellitus (juvenile or type I diabetes).

[0093] In another implementation, this treatment is associated with conditions mediated by PDE4 inhibition. These conditions include a variety of mammalian conditions, particularly inflammatory and / or allergic diseases, such as: asthma, chronic obstructive pulmonary disease (COPD) (e.g., chronic bronchitis and / or emphysema), atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, eosinophilic granulomatosis, psoriasis, rheumatoid arthritis, septic shock, ulcerative colitis, Crohn's disease, myocardial and cerebral reperfusion injury, chronic glomerulonephritis, endotoxin shock, adult respiratory distress syndrome, multiple sclerosis, cognitive impairment (e.g., in neurological disorders such as Alzheimer's disease), depression, or pain. Ulcerative colitis and / or Crohn's disease are often collectively referred to as inflammatory bowel disease.

[0094] In one embodiment of the invention, the inflammatory and / or allergic disease is chronic obstructive pulmonary disease (COPD), asthma, psoriasis, or rheumatoid arthritis in mammals (e.g., humans). In another embodiment, the invention provides a method for treating a disease selected from COPD, atopic dermatitis, psoriasis, IBD, and Crohn's disease.

[0095] Another embodiment of the present invention includes a method of treating a disease or condition by administering compound I to a subject in need or by administering a pharmaceutical composition comprising compound I to a subject in need, wherein the disease or condition is selected from hepatitis, non-alcoholic fatty liver disease, alcoholic fatty liver disease, cirrhosis, Wilson's disease, myasthenia gravis, idiopathic stomatitis diarrhea, inflammatory bowel disease, endocrine ophthalmopathy, Graves' disease, sarcoidosis, pancreatitis, nephritis, endotoxic shock, septic shock, hemodynamic shock, sepsis syndrome, ischemia-reperfusion injury, malaria, mycobacterial infection, meningitis, psoriasis, asthma, chronic obstructive pulmonary disease, eosinophilia, congestive heart failure, and fibrotic diseases. Cachexia, graft rejection, graft-versus-host disease, transplant rejection reaction, ankylosing spondylitis, autoimmune encephalomyelitis, hemolytic anemia, aplastic anemia, pure red cell anemia, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, Reiter's syndrome, non-infectious uveitis, autoimmune keratitis, keratoconjunctivitis sicca, vernal keratoconjunctivitis, psoriatic arthritis, atopic dermatitis, urticaria, viral infection, thrombosis, osteoarthritis, osteoporosis, emphysema, chronic bronchitis, allergic rhinitis, radiation injury, hyperoxia alveolar injury, periodontitis, non-insulin-dependent diabetes mellitus, and insulin-dependent diabetes mellitus. In a further embodiment, the disease or condition is hepatitis, wherein the hepatitis is alcoholic hepatitis, non-alcoholic hepatitis, viral hepatitis, drug-induced hepatitis, or autoimmune hepatitis. In another further embodiment, the disease or condition is inflammatory bowel disease, wherein the inflammatory bowel disease is ulcerative colitis, Crohn's disease, or autoimmune inflammatory bowel disease. In another further embodiment, the disease or condition is a fibrotic disease, wherein the fibrotic disease is cystic fibrosis, pulmonary fibrosis, liver fibrosis, kidney fibrosis, or interstitial pulmonary fibrosis. In another further embodiment, the disease or condition is a viral infection, wherein the viral infection is Severe Acute Respiratory Syndrome Coronavirus I, Severe Acute Respiratory Syndrome Coronavirus II, Middle East Respiratory Syndrome-associated Coronavirus, or Human Immunodeficiency Virus (HIV).

[0096] Another embodiment of the invention includes a method of treating a disease or condition by administering compound I or a pharmaceutical composition comprising compound I and a drug carrier to a subject in need, wherein the disease or condition is selected from: asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, eosinophilic granuloma, psoriasis, rheumatoid arthritis, septic shock, ulcerative colitis, Crohn's disease, myocardial and cerebral reperfusion injury, chronic glomerulonephritis, endotoxin shock, adult respiratory distress syndrome, neurological disorders, depression, or pain. In a further embodiment, the disease or condition is COPD, asthma, psoriasis, or rheumatoid arthritis. In another further embodiment, the disease or condition is COPD, wherein the COPD is chronic bronchitis or emphysema. In yet another further embodiment, the disease or condition is COPD, atopic dermatitis, or psoriasis. In another further embodiment, the disease or condition is a neurological disorder, wherein the neurological disorder is Parkinson's disease, Alzheimer's disease, or multiple sclerosis.

[0097] Compound I can also be administered in combination with other conventional anti-inflammatory agents or immunosuppressants, such as steroidal compounds, cyclooxygenase inhibitors, nonsteroidal anti-inflammatory drugs, TNF-α antibodies or other TNF-binding proteins, for example, acetylsalicylic acid, buprofen, diclofenac potassium, sulindac, diclofenac sodium, ketorolac tromethorphan, tometetin, ibuprofen, naproxen, naproxen sodium, thiamethoxam, flurbiprofen, mefenamic acid, fluniformic acid, meclofenamic acid, indomethacin, promethazine, ketoprofen, nabumetone, acetaminophen, piroxicam, tenoxicam, nimesulide, phenylbutazone. Tramadol, beclomethasone dipropionate, betamethasone, budesonide, fluticasone, mometasone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, celecoxib, rofecoxib, infliximab, leflunomide, etanercept, methotrexate, sulfasalazine, anti-lymphocyte immunoglobulin, anti-thymocyte immunoglobulin, azathioprine, cyclosporine, tacrolimus, ascomycin, rapamycin, adalimumab, moromumab-CD3, or other antibodies or fusion proteins that regulate T cell function, such as abatacept, afacilipecept, and efalizumab.

[0098] As described above, Compound I can be used alone or in combination with other therapeutic agents. This combination of pharmaceutically active agents can be administered together or alone, and when administered alone, administration can be simultaneous or sequential in any order. The concentration of the compound or agent and the relative timing of administration are chosen to achieve the desired therapeutic effect. Other therapeutic agents can be administered in conjunction with the following compositions: (1) a single pharmaceutical composition comprising two compounds; or (2) a single pharmaceutical composition, each of which comprises one of the compounds. Alternatively, the combination can be administered sequentially alone, with one therapeutic agent administered first, followed by the other, or vice versa. This sequential administration can be very close or very far in time. Compound I can be used to treat a variety of disorders and conditions, and therefore can be used in combination with a variety of other suitable therapeutic agents for the treatment or prevention of those disorders or conditions.

[0099] Example

[0100] Example 1. X-ray powder diffraction peaks of crystal form I

[0101] XRPD patterns were acquired using a PANalytical X'Pert PRO MPD diffractometer with a copper radiation incident beam generated by an Optix long-focus source. Cu Kα X-rays were focused onto the detector through the sample using an elliptical multilayer mirror. Prior to analysis, a silicon sample (NIST SRM 640e) was analyzed to verify that the observed Si 111 peak position was consistent with the NIST-certified position. The sample was sandwiched between 3 μm thick films, and transmission geometry analysis was performed. Beam stoppers, short antiscattering spreads, and antiscattering knife edges were used to minimize background from air. Soler slits for both the incident and diffracted beams were used to minimize broadening caused by axial divergence. Diffraction patterns were acquired using a scanning position-sensitive detector (X'Celerator) at a distance of 240 mm from the sample and data acquisition software version 5.5.

[0102] The characteristics of crystal form I are basically as follows: Figure 1 The XRPD curves shown are shown below, along with the XRPD data (Table 1).

[0103] Table 1.

[0104]

[0105] *Relative strength can vary depending on the size and shape of the crystal.

[0106] The representative values ​​for the angle 2θ of form I are 11.6, 12.0, and 24.1.

[0107] Example 2. XRPD Exponentiation of Form I

[0108] Using SSCI software (Triads) TM The high-resolution XRPD spectra were indexed. Indexing and structural refinement are computational studies. The consistency between the allowed peak positions and the observed peaks indicates that the unit cell determinations are consistent. Successful indexing of the spectra suggests that the sample is primarily composed of a single crystalline phase. The space groups consistent with the assigned extinction signs, unit cell parameters, and derived quantities are plotted in a table below, showing the provisional indexing scheme. To confirm the provisional indexing scheme, the molecular packing motif within the crystallographic unit cell must be determined. Molecular packing has not yet been attempted.

[0109] The unit cell parameters for form I are as follows:

[0110]

[0111] Example 3. Solid State of Form I 13 C NMR displacement

[0112] Acquired at ambient temperature on an Agilent DD2-400 spectrometer 13 C solid-state cross-polarized magic angle rotation (CP / MAS) NMR spectrum (Lamor frequency: 13 C = 100.549MHz 1 H = 399.812 MHz). The sample was loaded into a 4 mm PENCIL-type zirconia rotor and rotated at a frequency of 12 kHz according to the stated magic angle. During the acquisition time, high power (SPINAL-64) was used for phase modulation. 1 H-decoupling, utilizing 2.6 microseconds (90°) 1 The spectrum was acquired using an H-pulse width, a 5 ms tilt amplitude cross-polarization contact time, a 30 ms acquisition time, a 10 sec scan interval delay, a 45 kHz spectral width with 2678 data points, and 1600 co-amplification scans. Free induction attenuation (FID) was processed using Agilent VNMRJ 3.2A software with 65536 points and a 10 Hz exponential line broadening factor to improve the signal-to-noise ratio. The first three FID data points were back-predicted using a VNMR linear prediction algorithm to produce a flat baseline. The spectral peak chemical shifts were externally referenced to the carbonyl carbon resonance of glycine at 176.5 ppm.

[0113] The characteristics of crystal form I are basically as follows: Figure 4 The solid shown 13 C NMR spectroscopy and the following solid-state 13 C NMR displacement.

[0114]

[0115] (a) Carbonyl carbon resonance of reference glycine at 176.5 ppm in an external sample.

[0116] (b) Defined as peak height. Intensity can vary depending on the actual experimental parameters and the thermal history of the sample. Intensity is not necessarily quantitative.

[0117] A single representative solid of form I 13 The C NMR peaks are as follows:

[0118]

[0119] Example 4. FT-IR peak of Form I

[0120] IR spectra were acquired using a Nicolet 6700 Fourier transform infrared (FT-IR) spectrophotometer (Thermo Nicolet) equipped with an Ever-Glo mid / far-infrared source, a potassium bromide (KBr) spectrometer, and a deuterated tripylethyl sulfate (DTGS) detector. Wavelength validation was performed using a NIST SRM 1921b (polystyrene) instrument. A thunderdome-equipped attenuated total internal reflection (ATR) auxiliary instrument with a germanium (Ge) crystal was also used. TM Thermo Spectra-Tech was used for data acquisition. This spectrum represents the data at 4 cm⁻¹. -1 The data consisted of 256 co-amplification scans collected at a specific spectral resolution. The background dataset was obtained using pure germanium crystals. The Log 1 / R (R = reflectance) spectrum was obtained by taking the ratio of these two datasets.

[0121] The characteristics of crystal form I are basically as follows: Figure 5 The FT-IR spectrum and the following FT-IR peaks are shown.

[0122]

[0123]

[0124]

[0125] The following is a single representative FT-IR peak of Form I:

[0126] 768 1447 1626 1679 1731 1742

[0127] Example 5. Differential Scanning Calorimetry of Form I

[0128] Form I DSC (rate 10 °C / min, initial temperature -10 °C to final temperature 400 °C) showed that the first endothermic peak began at approximately 231 °C, peaked at approximately 263 °C, and ended at approximately 267 °C, and the second endothermic peak began at approximately 354 °C, peaked at approximately 360 °C, and ended at approximately 362 °C. Figure 2 ).

[0129] Example 6. Thermogravimetric analysis of Form I

[0130] Thermogravimetric analysis (TGA) of Form I (sample weight: 14.19 mg; initial temperature: 25 °C and final temperature: 350 °C; rate: 10.00 K / min) showed a weight loss of approximately 0.8% wt / wt from approximately 25 °C to approximately 127 °C, approximately 6.9% wt / wt from approximately 130 °C to approximately 300 °C, approximately 1.7% wt / wt from approximately 300 °C to approximately 350 °C, and a total weight loss of approximately 9.5% from approximately 25 °C to approximately 350 °C. Figure 3 ).

[0131] Example 7. Method for producing form I of compound I

[0132] The synthesis of compound I in form I can be accomplished in three steps. All reactions can be carried out using dry solvents under an inert atmosphere, such as nitrogen or argon.

[0133] Step 1: Ethyl-4-chloro-8-methoxyquinoline-3-carboxylate (1.0 eq) and trans-tert-butyl-4-aminocyclohexanecarboxylate hydrochloride (1.2 eq) were reacted in the presence of sodium bicarbonate (4.0 eq) and NMP (1-methyl-2-pyrrolidone). The intermediate from Step 1 precipitated from the reaction mixture by adding water. The resulting solid was collected by filtration and slurryed in water to remove residual inorganic matter and water-soluble organic solvents. The separated dry solid could be recrystallized in acetonitrile in high yield and purity.

[0134] Step 2: The intermediate from Step 1 (1.0 eq) was treated with sodium hydride (3.0 eq) in the presence of NMP, followed by the addition of 3-chlorophenyl isocyanate (3.0 eq). After the reaction was complete, the mixture was quenched with a mixture of NH4Cl-water-methanol, and the intermediate from Step 2 precipitated. The crude product was collected by filtration and washed with methanol and water. The crude solid could be purified sequentially using i) methanol, ii) methanol-tetrahydrofuran, and iii) acetone-tetrahydrofuran slurries.

[0135] Step 3: The intermediate (1.0 eq) from Step 2 was suspended in an acetic acid mixture, then 6 M HCl was added, and the resulting mixture was stirred at 20 ± 5 °C. After hydrolysis, the mixture was treated with water, and the resulting solid was collected by filtration. The starting material of Compound I can be slurried multiple times in 5 M HCl at 60 °C, then cooled to room temperature, and then filtered and washed with 5 M HCl to improve crystal purity and / or remove residual acetic acid.

Claims

1. A crystalline form of trans-4-[1-(3-chloro-phenyl)-7-methoxy-2,4-dioxo-3,4-dihydro-2H-pyrimidino[5,4-c]quinolin-3-yl]-cyclohexane carbamate, wherein the crystalline form is characterized by X-ray powder diffraction (XRPD) peaks at 2θ angles of 9.1° ± 0.2°, 11.6° ± 0.2°, 12.0° ± 0.2°, 14.2° ± 0.2°, 16.5° ± 0.2°, 19.0° ± 0.2°, 21.7° ± 0.2°, 22.4° ± 0.2°, and 24.1° ± 0.2°.

2. The crystal form according to claim 1, wherein the polymorphic purity of the crystal form is at least 95%.

3. A method for producing the crystal form according to claim 1, the method comprising: a) mixing trans-4-[1-(3-chloro-phenyl)-7-methoxy-2,4-dioxo-3,4-dihydro-2H-pyrimidino[5,4-c]quinolin-3-yl]cyclohexanecarboxylic acid or a salt thereof in an aqueous solution containing hydrochloric acid, wherein the aqueous solution has a temperature of at least 30°C; and b) Cool the mixture to below 30°C.

4. The method according to claim 3, wherein the aqueous solution containing hydrochloric acid is 5 M HCl.

5. The method according to claim 3 or 4, wherein the aqueous solution in step a) has a temperature of at least 50°C.

6. A pharmaceutical composition comprising the crystal form and a pharmaceutically acceptable carrier as described in claim 1.

7. Use of the crystal form according to claim 1 or the pharmaceutical composition according to claim 6 in the preparation of a medicament for treating asthma, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, emphysema, or chronic bronchitis in persons in need.

8. Use of the crystal form according to claim 1 or the pharmaceutical composition according to claim 6 in the preparation of a medicament for treating atopic dermatitis, psoriasis, psoriatic arthritis, ulcerative colitis, Crohn's disease, ankylosing spondylitis, rheumatoid arthritis (RA), Reiter's syndrome, or non-infectious uveitis in persons in need.

9. Use of the crystal form according to claim 1 or the pharmaceutical composition according to claim 6 in the preparation of a medicament for treating interstitial pulmonary fibrosis, pulmonary fibrosis, liver fibrosis, renal fibrosis, scleroderma or hyperoxia-induced alveolar injury in persons in need.

10. Use of the crystal form according to claim 1 or the pharmaceutical composition according to claim 6 in the preparation of a medicament for treating allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis or urticaria in persons in need.

11. The crystal form according to claim 1 or the pharmaceutical composition according to claim 6 in the preparation of a treatment for alcoholic hepatitis or drug-induced acute and fulminant hepatitis, alcoholic steatosis, non-alcoholic steatosis, viral hepatitis, non-viral hepatitis, cirrhosis, autoimmune hepatitis, chronic active hepatitis, Wilson's disease, myasthenia gravis, idiopathic stomatitis, endocrine ophthalmopathy, Graves' disease, sarcoidosis, primary biliary cirrhosis, pancreatitis, nephritis, endotoxic shock, septic shock, hemodynamic shock, sepsis syndrome, ischemia-reperfusion injury, malaria, mycobacterial infection, meningitis, eosinophilia, congestive heart failure, cystic fibrosis, malignant hepatitis, etc. Uses in medicines for conditions such as graft rejection, graft-versus-host disease, transplant rejection, autoimmune encephalomyelitis, hemolytic anemia, aplastic anemia, pure red cell anemia, idiopathic thrombocytopenic purpura, systemic lupus erythematosus (SLE), polychondritis, Wegener's granulomatosis, dermatomyositis, autoimmune keratitis, keratoconjunctivitis sicca, vernal keratoconjunctivitis, cancer, SARS infection, MERS infection, COVID-19 infection, human immunodeficiency virus (HIV) infection, cachexia, thrombosis, osteoarthritis (OA), osteoporosis, radiation injury, periodontitis, eosinophilic granulomatosis, septic shock, myocardial and cerebral reperfusion injury, chronic glomerulonephritis, or endotoxic shock.

12. Use of the crystal form according to claim 1 or the pharmaceutical composition according to claim 6 in the preparation of a medicament for treating Parkinson's disease, Alzheimer's disease, acute and chronic multiple sclerosis, cognitive impairment, depression or pain in persons in need.

13. Use of the crystal form according to claim 1 or the pharmaceutical composition according to claim 6 in the preparation of a medicament for treating type II or type I diabetes in persons in need.

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