Cocrystal of TYK2 inhibitor, and preparation method therefor and use thereof

Abstract

The present invention belongs to the field of pharmaceutical chemistry. Provided are a cocrystal of a TYK2 inhibitor, and a preparation method therefor and the use thereof, i.e., a cocrystal of compound A, and a preparation method therefor and the use thereof. Specifically, the present invention relates to a cocrystal formed by compound A and fumaric acid at a ratio of 2 : 1. The cocrystal has at least one of the following good characteristics: good stability, no tendency to disproportionate, good mechanical stress stability, good solubility, good dissolution, good crystal morphology, good flowability, high purity, good compression resistance, high bioavailability, high melting point, low hygroscopicity, and good processability such as good compressibility. The cocrystal can be stably stored, preventing a drug from dissociating or undergoing crystal transformation during development and storage. The preparation method is simple and reliable, rendering the cocrystal of great development value.

Description

A TYK2 inhibitor cocrystal, its preparation method and uses Citation of relevant applications

[0001] This application claims the full benefits of patent application No. 202411599018.8, filed with the State Intellectual Property Office of the People's Republic of China on November 11, 2024, the entire contents of which are incorporated herein by reference. Technical Field

[0002] This disclosure relates to the field of medicinal chemistry. Specifically, this disclosure relates to a cocrystal of a TYK2 inhibitor, its preparation method, and its use. Background Technology

[0003] A TYK2 inhibitor, chemically named 4-methyl-5-[3-methyl-7-(6-morpholin-4-ylpyridazin-3-ylamino)-3H-imidazo[4,5-b]pyridin-5-yloxy]pyridine-2-carbonitrile, hereinafter referred to as compound A, has the structure shown in formula (I):

[0004]

[0005] (I).

[0006] Compound A, disclosed in international application WO2019076716A1, possesses JAK (a family of tyrosine kinases) inhibitory activity, more specifically a TYK2 inhibitor. International application WO2023285405A1 discloses the use of compound A to treat inflammatory diseases and / or diseases associated with excessive secretion of IFNa and / or interferon (especially type I interferon-related diseases), IL-12, and / or IL-23. These diseases include systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, and / or Crohn's disease.

[0007] International application WO2024153617A1 discloses a cocrystalline form III formed by compound A and fumaric acid in a 1:1 ratio; it also discloses free crystal forms A and C, hydrochloride crystal forms and mesylate crystal forms, as well as multiple cocrystalline forms including maleate cocrystalline form I. Among these, the drug absorption effect of the fumaric acid cocrystalline form is better than that of the free form, and the drug absorption of the free form is better than that of the hydrochloride and mesylate crystal forms. Therefore, among the multiple solid forms disclosed in WO2024153617A1, the fumaric acid cocrystalline form III exhibits the best drug absorption.

[0008] However, the inventors of this disclosure have discovered that the existing fumaric acid eutectic form III is prone to disproportionation in aqueous systems, which is not conducive to storage and formulation processing. Therefore, given the shortcomings of the existing technology, in order to meet the pharmaceutical needs of compound A, it is necessary to develop compound A or its salt or eutectic solid form with more advantageous properties and corresponding preparation methods. Summary of the Invention

[0009] This disclosure provides a cocrystal formed by TYK2 inhibitor compound A and fumaric acid in a 2:1 ratio, which has at least one of the following excellent properties: good stability, non-disproportionation, good mechanical stress stability, good solubility, good dissolution, good crystal morphology, good flowability, high purity, good compressibility, high bioavailability, high melting point, low hygroscopicity, good processability (e.g., good compressibility), stable storage, and avoidance of drug dissociation or transcrystallization during development and storage. The preparation method is simple and reliable, and it has great development value.

[0010] One aspect of this disclosure is to provide a eutectic form of compound A and fumaric acid, A28-1 (hereinafter referred to as eutectic A28-1), wherein the molar ratio of compound A and fumaric acid is 2:1, and the eutectic A28-1, when subjected to Cu-Kα radiation, exhibits characteristic peaks at one, two, or three of the following X-ray powder diffraction (XRPD) patterns in 2θ angles: 8.7°±0.2°, 14.4°±0.2°, and 15.9°±0.2°.

[0011] In the preferred embodiment of this disclosure, Cu-Kα radiation is used, and the X-ray powder diffraction pattern of the eutectic A28-1 has characteristic peaks at 8.7°±0.2°, 14.4°±0.2° and 15.9°±0.2°2θ.

[0012] In the preferred embodiment of this disclosure, Cu-Kα radiation is used, and the X-ray powder diffraction pattern of the eutectic A28-1 has characteristic peaks at at least one of 12.5°±0.2°, 13.4°±0.2°, and 17.5°±0.2°2θ.

[0013] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the eutectic A28-1 shows characteristic peaks at two or three locations in 12.5°±0.2°, 13.4°±0.2°, and 17.5°±0.2°2θ.

[0014] In the preferred embodiment of this disclosure, Cu-Kα radiation is used, and the X-ray powder diffraction pattern of the eutectic A28-1 has characteristic peaks at at least one of 5.2°±0.2°, 5.9°±0.2°, and 19.7°±0.2°2θ.

[0015] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the eutectic A28-1 showed characteristic peaks at two or three of the following locations: 5.2°±0.2°, 5.9°±0.2°, and 19.7°±0.2°2θ.

[0016] Non-limitingly, using Cu-Kα radiation, the X-ray powder diffraction pattern of the eutectic A28-1 exhibits characteristic peaks at 8.7°±0.2°, 14.4°±0.2°, 15.9°±0.2°, 12.5°±0.2°, 13.4°±0.2°, 17.5°±0.2°, 5.2°±0.2°, 5.9°±0.2°, and 19.7°±0.2°2θ.

[0017] On the other hand, this disclosure provides a eutectic A28-1 of compound A and fumaric acid, wherein the molar ratio of compound A and fumaric acid is 2:1. Using Cu-Kα radiation, the X-ray powder diffraction pattern of the eutectic A28-1 has characteristic peaks at any 1, 2, 3, 4, 5, 6, 7, 8, or 9 of the following 2θ values: 8.7°±0.2°, 14.4°±0.2°, 15.9°±0.2°, 12.5°±0.2°, 13.4°±0.2°, 17.5°±0.2°, 5.2°±0.2°, 5.9°±0.2°, and 19.7°±0.2°.

[0018] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the eutectic A28-1 showed a characteristic peak at 8.7°±0.2°2θ.

[0019] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the eutectic A28-1 exhibits characteristic peaks at 8.7°±0.2° and 14.4°±0.2°2θ.

[0020] Furthermore, using Cu-Kα radiation, the X-ray powder diffraction pattern of the eutectic A28-1 showed characteristic peaks at 8.7°±0.2° and 15.9°±0.2°2θ.

[0021] Non-limiting, the eutectic A28-1 has an X-ray powder diffraction pattern basically as shown in Figure 1 or Figure 4.

[0022] Without limitation, the eutectic A28-1 is essentially pure.

[0023] Preferably, the eutectic A28-1 has a purity of greater than 90%; more preferably, it has a purity of greater than 95%; and more preferably, it has a purity of greater than 99%.

[0024] Without limitation, the eutectic A28-1 is a hydrate.

[0025] Non-limitingly, the eutectic A28-1 has a TGA spectrum basically as shown in Figure 2, showing a mass loss of about 2.9% between 100°C and 175°C and a mass loss of about 11.6% between 175°C and 275°C.

[0026] Without limitation, the eutectic A28-1 has a DSC pattern essentially as shown in Figure 3.

[0027] In another aspect, this disclosure provides a method for preparing eutectic A28-1, wherein the preparation method is selected from any of the following methods:

[0028] 1) Dissolve the eutectic of compound A and fumaric acid in N,N-dimethylformamide, trifluoroethanol or dimethyl sulfoxide, add water or an aqueous solvent to the solution, precipitate the solid, separate and dry it to obtain eutectic A28-1;

[0029] Preferably, the eutectic of compound A and fumaric acid is a monofumaric acid eutectic of compound A.

[0030] In some embodiments, the eutectic of compound A and fumaric acid is in form III;

[0031] Preferably, the proportion of water in the aqueous solvent is arbitrary;

[0032] Preferably, the aqueous solvent is an ether, alkane, or ester;

[0033] Preferably, the ether is selected from any one of isopropyl ether, diethyl ether, or methyl tert-butyl ether, or a mixture thereof; the alkane is selected from any one of methane, n-heptane, or methylcyclohexane, or a mixture thereof; and the ester is selected from any one of ethyl acetate, methyl acetate, or butyl acetate, or a mixture thereof.

[0034] Preferably, the addition of water or an aqueous solvent is accompanied by stirring;

[0035] Preferably, the drying is vacuum drying, and the drying temperature is 30-60℃, preferably 40℃.

[0036] 2) Compound A and fumaric acid were mixed and stirred in an aqueous alcohol solvent, a solid was precipitated, centrifuged and dried to obtain eutectic A28-1;

[0037] Preferably, the alcohol solvent is selected from any one of ethanol, methanol, isopropanol, and n-propanol, or a mixture thereof;

[0038] In some specific embodiments, the alcohol solvent is selected from ethanol;

[0039] Preferably, the molar ratio of compound A to fumaric acid is 2:1 to 1:1;

[0040] In some specific embodiments, the molar ratio of compound A to fumaric acid is 2:1;

[0041] Preferably, the stirring time is ≥5 min, and the stirring temperature is 4℃-80℃;

[0042] In some embodiments, the stirring time is 4 days and the stirring temperature is room temperature;

[0043] Preferably, the drying temperature is 30℃-80℃, more preferably 40℃.

[0044] The eutectic A28-1 described in this disclosure has the following beneficial effects:

[0045] 1) Good stability. The eutectic A28-1 described in this disclosure maintains its crystal form unchanged and its chemical purity remains essentially unchanged after 12 months of long-term (25℃ / 60%RH / open) and accelerated (40℃ / 75%RH / open) storage conditions. This indicates that the eutectic A28-1 of this disclosure can maintain good physicochemical stability under both long-term and accelerated conditions, which is beneficial for drug storage.

[0046] Furthermore, the eutectic A28-1 of this disclosure maintains its crystal form and crystallinity before and after grinding, while the crystallinity of the prior art eutectic form III decreases after grinding. This indicates that the eutectic A28-1 of this disclosure has superior mechanical stability. In the process of pharmaceutical preparation, it is often necessary to grind and pulverize the active pharmaceutical ingredient. Good mechanical stability can reduce the risk of decrease in crystallinity and crystal transformation of the active pharmaceutical ingredient during the pharmaceutical preparation process.

[0047] Furthermore, the eutectic A28-1 disclosed herein is stable in aqueous systems, high-temperature and high-humidity environments, and different pH media, and will not undergo disproportionation reactions, which is more conducive to the storage of raw materials and the processing of formulations, ensuring the quality and bioavailability of drugs.

[0048] 2) Good solubility. In pH 1.0 hydrochloric acid buffer, the solubility of the eutectic A28-1 of this disclosure is 1.3 times that of the prior art eutectic form III, indicating that the eutectic A28-1 of this disclosure may have better bioavailability.

[0049] 3) Excellent dissolution. Compared with the prior art, the eutectic A28-1 of this disclosure has a superior intrinsic dissolution rate. In a hydrochloric acid solution at pH 1.0, the intrinsic dissolution rate of the eutectic A28-1 of this disclosure is 1.6 times that of the prior art eutectic form III. Intrinsic dissolution rate is an important prerequisite for drug absorption. A high dissolution rate allows the drug to quickly reach its maximum concentration in plasma after administration, thereby ensuring rapid onset of action.

[0050] 4) Small particle size. The particle size of the eutectic A28-1 disclosed herein is significantly smaller than that of the prior art eutectic form III. Smaller particle size helps improve the bioavailability of the drug, especially for poorly soluble drugs. Smaller particle size can increase the contact area between the drug and the solvent, promoting drug solubility and absorption. In addition, PLM analysis shows that the eutectic A28-1 of this disclosure is a blocky crystal with good flowability, while the prior art eutectic form III is a needle-like crystal with poor flowability, which is not conducive to formulation processing.

[0051] 5) High purity. The eutectic A28-1 provided in this disclosure has a purity of over 99%, which is beneficial for industrial production.

[0052] 6) Good crystallinity. The eutectic A28-1 provided in this disclosure has good crystallinity and is suitable for pharmaceutical use.

[0053] Another aspect of this disclosure is to provide a pharmaceutical composition comprising a therapeutically effective amount of the eutectic A28-1 described in this disclosure, and at least one pharmaceutically acceptable carrier.

[0054] The pharmaceutically acceptable carrier can be selected based on the method and route of administration.

[0055] Without limitation, suitable carriers may include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose.

[0056] Without limitation, the pharmaceutical composition may also contain lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methylparaben and propylparaben; sweeteners; and flavoring agents.

[0057] Non-limiting, the pharmaceutical composition may also comprise one or more pH adjusters or buffers, for example: acids, such as any one or a combination of acetic acid, boric acid, citric acid, fumaric acid, maleic acid, tartaric acid, malic acid, lactic acid, phosphoric acid, hydrochloric acid; or bases, such as any one or a combination of sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, tris(hydroxymethyl)aminomethane; or buffers, such as citrate / glucose, sodium bicarbonate, ammonium chloride, and the like; such buffers used as bases may have balancing ions other than sodium, such as potassium, magnesium, calcium, ammonium, and other balancing ions; and other amounts required to maintain the pH of the components within an acceptable range, in solutions or solids comprising such acids, bases, and buffers.

[0058] Without limitation, the routes of administration of the pharmaceutical composition include oral, sublingual, buccal, transdermal, intradermal, intramuscular, parenteral, intravenous, intra-arterial, intracranial, subcutaneous, intraorbital, intravenous, intraspinal, intraperitoneal, intranasal, inhalation, and topical application.

[0059] Another aspect of this disclosure is to provide a formulation prepared from the above-described pharmaceutical composition, wherein the formulation is selected from oral and parenteral formulations.

[0060] In the preferred technical solutions disclosed herein, the formulations are tablets, capsules, suspensions, powders, sustained-release formulations, immediate-release formulations, pills, suppositories, granules, fine granules / tablets, capsules, flat capsules, tinctures, elixirs, emulsions, creams, aerosols, gels, solutions, and syrups.

[0061] In the preferred embodiment of this disclosure, the formulation is an oral formulation.

[0062] In the preferred embodiment of this disclosure, the formulation is in the form of tablets, capsules, or suspension. In the preferred embodiment of this disclosure, the formulation is in the form of capsules. In the preferred embodiment of this disclosure, a unit dose of the composition or formulation contains a eutectic A28-1 equivalent to 80 mg-200 mg of the free base of compound A.

[0063] In some embodiments, the unit dose of the composition or formulation contains a eutectic A28-1 equivalent to 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 175 mg, 180 mg, 190 mg, or 200 mg of the free base of compound A.

[0064] In some embodiments, eutectic A28-1 can be mixed with a dry gelatin binder, and a small amount of magnesium stearate can be added as a lubricant. The mixture can be formed into tablets in a tableting machine.

[0065] In some embodiments, eutectic A28-1 can be mixed with a starch diluent, and the mixture can be filled into capsules.

[0066] In some embodiments, eutectic A28-1 can be mixed with sucrose and xanthan gum, and the resulting mixture can be blended through a 10-mesh US sieve. It is then mixed with a previously prepared solution of microcrystalline cellulose and sodium carboxymethyl cellulose in water. Sodium benzoate, flavoring agents and coloring agents can be diluted with water and added with stirring. Sufficient water can then be added with stirring, and more sufficient water can be added to produce a suitable total volume.

[0067] Another aspect of this disclosure is the use of a therapeutically effective amount of the eutectic A28-1 described herein or the pharmaceutical composition or formulation thereof in the preparation of a medicament for the treatment or prevention of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving chondrodysplasia, congenital chondrodysplasia, and / or diseases associated with excessive secretion of IFNα, IL12, and / or IL23.

[0068] Preferably, the therapeutically effective dose is administered at a total daily dose of at least 80 mg to 200 mg, more preferably at least 90 mg to 150 mg or 150 mg to 200 mg per day.

[0069] In some embodiments, the therapeutically effective dose is a total daily dose of at least 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 175 mg, 180 mg, 190 mg, or 200 mg per day.

[0070] Preferably, the total daily dose is administered at a dose once daily (qd).

[0071] Preferably, the allergic disease is asthma.

[0072] Preferably, the inflammatory disease is rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), primary cholangitis (PBC), primary sclerosing cholangitis (PSC), or inflammatory bowel disease. More preferably, the inflammatory disease is rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), or inflammatory bowel disease.

[0073] Preferably, the metabolic disease is type II diabetes and / or obesity.

[0074] Preferably, the autoimmune disease is cryptothermal protein-associated periodic syndrome (CAPS), familial Mediterranean fever (FMF), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Behcets, systemic juvenile idiopathic arthritis (SJIA), or Still's disease.

[0075] Preferably, the proliferative disease is cancer, leukemia, multiple myeloma, or psoriasis.

[0076] Preferably, the transplant rejection is graft-versus-host disease.

[0077] Preferably, the disease involving cartilage conversion disorder is ankylosing spondylitis.

[0078] Preferably, the congenital cartilage malformation is microtia, auria, and / or epiphyseal cartilage developmental abnormalities.

[0079] Preferably, the diseases associated with excessive secretion of IFNα, IL12 and / or IL23 are systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, multiple sclerosis and / or Crohn's disease.

[0080] Another aspect of this disclosure is to provide a method for treating or preventing allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving chondrodysplasia, congenital cartilage malformations, and / or diseases associated with excessive secretion of IFNα, IL12, and / or IL23, comprising administering to a patient a therapeutically effective amount of the eutectic A28-1 described in this disclosure or the pharmaceutical composition or formulation described herein.

[0081] Preferably, the allergic disease is asthma.

[0082] Preferably, the inflammatory disease is rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), primary cholangitis (PBC), primary sclerosing cholangitis (PSC), or inflammatory bowel disease. More preferably, the inflammatory disease is rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), or inflammatory bowel disease.

[0083] Preferably, the metabolic disease is type II diabetes and / or obesity.

[0084] Preferably, the autoimmune disease is cryptothermal protein-associated periodic syndrome (CAPS), familial Mediterranean fever (FMF), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Behcets, systemic juvenile idiopathic arthritis (SJIA), or Still's disease.

[0085] Preferably, the proliferative disease is cancer, leukemia, multiple myeloma, or psoriasis.

[0086] Preferably, the transplant rejection is graft-versus-host disease.

[0087] Preferably, the disease involving cartilage conversion disorder is ankylosing spondylitis.

[0088] Preferably, the congenital cartilage malformation is microtia, auria, and / or epiphyseal cartilage developmental abnormalities.

[0089] Preferably, the diseases associated with excessive secretion of IFNα, IL12 and / or IL23 are systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, multiple sclerosis and / or Crohn's disease.

[0090] Preferably, the therapeutically effective dose is administered at a total daily dose of at least 80 mg to 200 mg, more preferably at least 90 mg to 150 mg or 150 mg to 200 mg per day.

[0091] In some embodiments, the therapeutically effective dose is a total daily dose of at least 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 175 mg, 180 mg, 190 mg, or 200 mg per day.

[0092] Preferably, the total daily dose is administered at a dose once daily (qd).

[0093] In specific implementation schemes, when using the eutectic A28-1 described in this disclosure to treat patients, concurrent or co-administered use with one or more CYP inhibitors and / or P-gp inhibitors should be avoided, contraindicated, or interrupted.

[0094] Preferably, the treatment method includes the step of discontinuing or treating one or more CYP inhibitors and / or P-gp inhibitors before or simultaneously with the start of treatment.

[0095] Preferably, the treatment method includes the step of discontinuing the use of one or more CYP inhibitors and / or P-gp inhibitors at least 12 hours, preferably at least 24 hours, before starting treatment.

[0096] Preferably, the treatment method further includes concurrent or co-administered use with a drug of the same class or mechanism of action, or a known suitable alternative to the corresponding therapy, and is not a CYP inhibitor and / or a P-gp inhibitor, particularly not a CYP3A4 inhibitor and / or not a P-gp inhibitor, and more particularly not a strong CYP3A4 inhibitor and / or not a strong P-gp inhibitor.

[0097] Preferably, the CYP inhibitor is a CYP3A4 inhibitor, and is derived from Atazanavir, Boceprevir, Clarithromycin, Cobicistat, Conivaptan, Danoprevir, Darunavir, Delaviridine, Diltiazem, Elvitegravir, grapefruit juice, Idelalisib, Indinavir, Itraconazole, Ketoconazole, Lonafamib, Lopinavir, Nefazodone, Nelfmavir, Nilotinib, Posaconazole, Ritonavir, Saquinavir, Stiripentol, Telithromycin, etc. Tipranavir, Troleandomycin, Voriconazole, Aprepitant, Ciprofloxacin, Crizotinib, Cyclosporine, Dronedarone, Erythromycin, Fluconazole, Fluvoxamine, Imatinib, Verapa mil, Chlorzoxazone, Cilostazol, Cimetidine, Fosaprepitant, Istradefylline, Ivacaftor, Lomitapide, Ranitidine, Ranolazine, Ticagrelor, (S)-omeprazole (esomeprazole)- High dose, ACT-178882, ACT- 539313, Almorexant, AMD070, ANS-6637, Apararenone, ASP8477, Atorvastatin, AZD2327, Azithromycin, Berberine, Berotralstat, Bicalutamide, Brodalumab, Casopit ant, Ceritinib, Clotrimazole, cranberry juice, Duvelisib, Entrectinib, Evacetrapid, Everolimus, Faldaprevir, Fedratinib, Fenebrutinib, FK1706, Fostamatinib, Ginkgo (Ginkgo biloba), Glecaprevir / Pibrentasvir, Goldenseal (HydrastisThe following are drug names selected from: canadensis, Grazoprevir (a component of Zepatier), GSK2248761, Isavuconazole, Fapatinib, Farotrectinib, FCF161, Fefamulin, Fetermovir, Fumateperone, Furasidone, Ml00240, Mibefradil, Netupitant, obeticholic acid, Olaparib, Osilodrostat, Palbociclib, Pazopanib, Posaconazole, Propiverine, Ravuconazole, Ribociclib, Rimegepant, Roxithromycin, Rucaparib, Schisandra sphenanthera, Scutellarin (Breviscapine), Selpercatinib, Simeprevir, Suvorexant, Tabimorebn, Tacrolimus, Telaprevir, Teriflunomide, Tofisopam, Tucatinib, Verapamil, and Voxelotor.

[0098] Another aspect of this disclosure is to provide a combination of the eutectic A28-1 described herein or the pharmaceutical composition or formulation described herein with other pharmaceuticals.

[0099] As used herein, unless otherwise specified, the singular forms “a / an” and “the” include plural individuals and things.

[0100] When considered by those skilled in the art, the term “about” means having a value that falls within an acceptable standard of average error.

[0101] As used herein, the term "therapeutic effective amount" refers to the amount of a compound administered that will, to some extent, alleviate one or more symptoms of the disease being treated.

[0102] As used herein, the term “dosage” or “unit dose” refers to the equivalent weight of the applied free base compound A, i.e., the weight excluding any salts, solvates, or eutectic counterparts or components.

[0103] Unless otherwise specified, the term "treatment" as used herein means reversing, alleviating, or preventing the development of the condition or symptom, or one or more symptoms of such condition or symptom. Unless otherwise specified, the term "treatment" as used herein refers to therapeutic acts as defined above as "treating." The term "treatment" also includes adjunctive and neoadjunctive therapies for the subject.

[0104] Unless otherwise specified, “room temperature” as used in this disclosure refers to a temperature of 10 to 30°C.

[0105] The "separation" can be performed using conventional methods in the art, such as centrifugation or filtration. Reduced-pressure filtration, in particular, typically involves suction filtration at room temperature under pressure less than atmospheric pressure.

[0106] The "drying" can be accomplished using conventional techniques in the field, such as room temperature drying, forced-air drying, or vacuum drying, or it can be carried out under reduced or no reduced pressure. The drying instruments and methods are not limited and can include fume hoods, forced-air ovens, spray dryers, fluidized bed dryers, or vacuum ovens; it can also be carried out under reduced or no reduced pressure.

[0107] The "relative intensity (I%)" mentioned above is represented by a specific numerical value in a specific XRPD pattern. Based on the anisotropic properties of crystals and the principle of X-ray powder diffraction, the relative intensity value of diffraction peaks of the same crystal form will fluctuate with the preferred orientation of the sample. The common sense that this fluctuation does not affect the judgment of the same crystal form should be accepted by those skilled in the art.

[0108] Unless otherwise specified, the ratios mentioned in this disclosure, when referring to liquids and solids, are mass-to-volume ratios, and when referring to liquids and liquids, are volume ratios.

[0109] Attached Figure Description

[0110] Figure 1 shows the XRPD pattern of the eutectic A28-1 prepared in Example 1;

[0111] Figure 2 shows the TGA spectrum of the eutectic A28-1 prepared in Example 1;

[0112] Figure 3 shows the DSC spectrum of the eutectic A28-1 prepared in Example 1;

[0113] Figure 4 shows the XRPD pattern of the eutectic A28-1 prepared in Example 5;

[0114] Figure 5 shows the XRPD stack-up images of eutectic A28-1 in Example 6 before and after long-term (25℃ / 60%RH / open) and accelerated (40℃ / 75%RH / open) placement.

[0115] Figure 6 shows the XRPD overlay images of eutectic A28-1 before and after grinding in Example 7;

[0116] Figure 7 is an XRPD overlay of the prior art eutectic form III before and after grinding in Example 7;

[0117] Figure 8 is an XRPD overlay of eutectic A28-1 in solvent 2 before and after reaction in Example 8;

[0118] Figure 9 is an XRPD overlay of the prior art eutectic form III in solvent 2 before and after reaction in Example 8;

[0119] Figure 10 is a PLM diagram of eutectic A28-1 in Example 11;

[0120] Figure 11 is a PLM diagram of the prior art eutectic form III in Example 11.

[0121] Detailed Implementation

[0122] The following examples will help to further understand this disclosure, but are not intended to limit the scope of this disclosure.

[0123] Testing instruments and methods:

[0124]

[0125] HPLC determination method: Chromatograph model: Ultimate3000, chromatographic column: C18 3.5μm 4.6*250mm, column temperature: 30℃, flow rate: 1.1mL / min, detection wavelength: 254nm, run time: 30min, mobile phase A: 0.1% TFA aqueous solution; mobile phase B: 0.1% TFA acetonitrile, gradient method detection.

[0126] In this disclosure, the starting material compound A or fumaric acid eutectic (form III) can be obtained commercially or prepared by existing techniques, such as those described in WO2019076716A1 or WO2024153617A1.

[0127] Example 1: Preparation of the eutectic A28-1 of compound A and fumaric acid

[0128] Take about 20 mg of compound A fumaric acid eutectic form III, add 0.4 mL of N,N-dimethylacetamide to dissolve it, add 4.0 mL of water while stirring at room temperature, precipitate the solid, centrifuge, and dry under vacuum at 40 °C overnight to obtain eutectic A28-1.

[0129] The XRPD data were measured and are shown in the table below:

[0130]

[0131] Its XRPD map is shown in Figure 1.

[0132] Its TGA spectrum is shown in Figure 2, which shows a mass loss of about 2.9% between 100℃ and 175℃, corresponding to about 1 molecule of water, and a mass loss of about 11.6% between 175℃ and 275℃, corresponding to about 0.5 molecules of fumaric acid.

[0133] Its DSC spectrum is shown in Figure 3.

[0134] The eutectic A28-1 prepared in this embodiment is a hydrate.

[0135] Example 2: Preparation of the eutectic A28-1 of compound A and fumaric acid

[0136] Take about 20 mg of compound A fumaric acid eutectic form III, add 0.4 mL of N,N-dimethylacetamide to dissolve it, add 4.0 mL of isopropyl ether and a small amount of water while stirring at room temperature, precipitate the solid, centrifuge, and dry under vacuum at 40 °C overnight to obtain eutectic A28-1.

[0137] Example 3: Preparation of the eutectic A28-1 of compound A and fumaric acid

[0138] Take about 20 mg of compound A fumaric acid eutectic form III, add 1.8 mL of trifluoroethanol to dissolve it, add 4.0 mL of water under stirring at room temperature, stir for about 2 h, precipitate solid, centrifuge, and vacuum dry at 40 °C overnight to obtain eutectic A28-1.

[0139] Example 4: Preparation of the eutectic A28-1 of compound A and fumaric acid

[0140] Take about 20 mg of compound A fumaric acid eutectic form III, add 0.4 mL of dimethyl sulfoxide to dissolve it, add 4.0 mL of water while stirring at room temperature, precipitate the solid, centrifuge, and dry under vacuum at 40 °C overnight to obtain eutectic A28-1.

[0141] Example 5: Preparation of the eutectic A28-1 of compound A and fumaric acid

[0142] Approximately 47 mg of compound A was suspended in 3 mL of ethanol, and approximately 7 mg of fumaric acid was prepared in 0.3 mL of ethanol to form solution 1. Solution 1 was added dropwise to suspension 1 at 40 °C, stirred for 4 days, centrifuged, and the resulting solid was dried under vacuum at 40 °C for 2.5 hours to obtain eutectic A28-1.

[0143] The XRPD spectrum of the sample is shown in Figure 4.

[0144] Example 6: Physical and Chemical Stability Study

[0145] An appropriate amount of the fumaric acid eutectic sample A28-1 of compound A of this disclosure was placed under long-term (25℃ / 60%RH / open) and accelerated (40℃ / 75%RH / open) conditions, and the chemical purity and crystal form were determined periodically by HPLC and XRPD. The results are shown in Table 1 and Figure 5.

[0146] Table 1

[0147]

[0148] The results show that the eutectic A28-1 can maintain its crystal form for at least 12 months under long-term (25℃ / 60%RH / open) and accelerated (40℃ / 75%RH / open) conditions, and its chemical purity remains basically unchanged, demonstrating good physical and chemical stability.

[0149] Example 7: Study on grinding stability

[0150] Appropriate amounts of the eutectic form A28-1 of compound A of this disclosure and the eutectic form III of fumaric acid in the prior art were taken and placed in a mortar, manually ground, and the XRPD of the samples before and after grinding was tested. The XRPD spectra before and after grinding are shown in Figures 6-7.

[0151] The results show that the eutectic A28-1 of this disclosure retains its crystal form and crystallinity unchanged before and after grinding, while the crystallinity of the prior art eutectic form III decreases after grinding, indicating that the eutectic A28-1 of this disclosure has superior mechanical stability.

[0152] Example 8: Study on the disproportionation of eutectic

[0153] Approximately 20 mg of the eutectic form A28-1 of compound A of this disclosure and the eutectic form III of fumaric acid in the prior art were taken respectively. According to Table 2, solvent 1 was added to obtain a clear solution. Solvent 2 was slowly added under stirring. After the solid precipitated, it was centrifuged and the solid was used for XRPD characterization. The results are shown in Table 2 and Figures 8-9.

[0154] Table 2

[0155]

[0156] The results show that the eutectic A28-1 of this disclosure retains its crystal form unchanged in the solvent systems in Table 2, while the eutectic form III of the prior art disproportionates to the eutectic A28-1 of this disclosure in the solvents in Table 2.

[0157] In addition, sodium stearate fumarate is often added to pharmaceutical preparations as a lubricant for tablets and capsules. The inventors of this disclosure mixed the eutectic A28-1 of this disclosure and the prior art eutectic form III with sodium stearate, respectively, and placed them in a high-temperature and high-humidity environment (75℃ / 75%RH) for 10 days, then analyzed the XRPD spectra before and after the storage period. The results showed that the diffraction peak positions and the number of diffraction peaks of the eutectic A28-1 of this disclosure remained unchanged in the mixture, indicating good stability. However, the prior art eutectic form III showed a peak of the free state form A in its XRPD spectra on the 10th day after storage, indicating that the prior art eutectic form III underwent disproportionation.

[0158] Example 9: Solubility Study

[0159] Samples of compound A of this disclosure, the cocrystal of fumaric acid A28-1, and the prior art cocrystal of fumaric acid III were prepared into saturated solutions in water, pH 1.0 hydrochloric acid buffer, and pH 4.5 hydrochloric acid buffer at 37°C. The solutions were filtered after 1 hour and 2 hours, respectively, and the actual concentration of the sample in the saturated solution was determined by high-performance liquid chromatography (HPLC). The crystal form of the solid before and after the experiment was characterized by XRPD. The results are shown in Table 3.

[0160] Table 3

[0161]

[0162] The results show that the eutectic A28-1 of this disclosure does not undergo disproportionation or transcrystallization in the three media mentioned above, while the prior art eutectic form III disproportionates the disclosed eutectic A28-1 in both water and pH 4.5 hydrochloric acid buffer. Furthermore, in pH 1.0 hydrochloric acid buffer, the solubility of the disclosed eutectic A28-1 is 1.3 times that of the prior art eutectic form III, indicating that the disclosed eutectic A28-1 may have superior bioavailability.

[0163] Example 10: Inherent Dissolution Study

[0164] Approximately 40 mg of samples of compound A of this disclosure, the eutectic form A28-1 of fumaric acid, and the prior art eutectic form III of fumaric acid were taken and placed in an intrinsic dissolution mold. The mold was pressed into a thin sheet under a pressure of 2 MPa for 30 seconds. The mold containing the sample was then placed on a dissolution apparatus to detect the intrinsic dissolution rate. The test conditions are shown in Table 4, and the dissolution data are shown in Table 5. The slope was calculated based on the measurement points between 0 and 120 min, expressed in mg / mL. The intrinsic dissolution rate (IDR) was further calculated based on the slope, expressed in mg / min / cm³. 2The IDR results are shown in Table 6.

[0165] Table 4

[0166]

[0167] Table 5

[0168]

[0169] Table 6

[0170]

[0171] The results show that the inherent dissolution rate of the eutectic A28-1 disclosed herein is 1.6 times that of the prior art eutectic form III.

[0172] Example 11: Particle size and morphology study

[0173] The particle size and PLM of the eutectic form A28-1 of compound A and fumaric acid of the present disclosure and the eutectic form III of fumaric acid of the prior art were respectively analyzed, and the results are shown in Table 7 and Figures 10-11.

[0174] Table 7

[0175]

[0176] The results show that the particle size of the eutectic A28-1 disclosed herein is significantly smaller than that of the prior art eutectic form III. Smaller particle size helps improve drug bioavailability, especially for poorly soluble drugs, as it increases the contact area between the drug and solvent, promoting drug dissolution and absorption. Furthermore, PLM analysis reveals that the eutectic A28-1 of this disclosure is a blocky crystal with good flowability, while the prior art eutectic form III is a needle-like crystal with poor flowability, which is detrimental to formulation processing.

[0177] The above description is merely a specific embodiment of this disclosure, but the scope of protection of this disclosure is not limited thereto. Any variations or substitutions that can be conceived by those skilled in the art within the scope of the technology disclosed in this disclosure without inventive effort should be included within the scope of protection of this disclosure. Therefore, the scope of protection of this disclosure should be determined by the scope defined in the claims.

Claims

1. A eutectic A28-1 of compound A and fumaric acid, wherein the molar ratio of compound A to fumaric acid is 2:1, and the X-ray powder diffraction pattern of the eutectic A28-1, expressed in 2θ angles, shows characteristic peaks at one, two, or three of the following locations: 8.7°±0.2°, 14.4°±0.2°, and 15.9°±0.2°.

2. The eutectic A28-1 according to claim 1, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction pattern of the eutectic A28-1 shows characteristic peaks at 8.7°±0.2°, 14.4°±0.2°, and 15.9°±0.2° 2θ.

3. The eutectic A28-1 according to claim 1 or 2, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction pattern of the eutectic A28-1 has a characteristic peak at at least one of 12.5°±0.2°, 13.4°±0.2° and 17.5°±0.2°2θ; Preferably, using Cu-Kα radiation, the X-ray powder diffraction pattern of the eutectic A28-1 has characteristic peaks at two or three of the following locations: 12.5°±0.2°, 13.4°±0.2° 2θ, and 17.5°±0.2° 2θ.

4. The eutectic A28-1 according to claim 1 or 2, characterized in that, Using Cu-Kα radiation, the X-ray powder diffraction pattern of the eutectic A28-1 has a characteristic peak at at least one of 5.2°±0.2°, 5.9°±0.2° and 19.7°±0.2° 2θ; Preferably, using Cu-Kα radiation, the X-ray powder diffraction pattern of the eutectic A28-1 has characteristic peaks at two or three of the following 2θ values: 5.2°±0.2°, 5.9°±0.2°, and 19.7°±0.2°.

5. The eutectic A28-1 according to claim 1 or 2, characterized in that, The eutectic A28-1 has an X-ray powder diffraction pattern as shown in Figure 1 or Figure 4. Preferably, the eutectic A28-1 has an X-ray powder diffraction pattern as shown in Figure 1; 6. The eutectic A28-1 according to claim 1 or 2, characterized in that, The eutectic A28-1 is essentially pure.

7. The eutectic A28-1 according to claim 1 or 2, characterized in that, The eutectic A28-1 is a hydrate.

8. The eutectic A28-1 according to claim 1 or 2, characterized in that, The eutectic A28-1 has a TGA pattern as shown in Figure 2.

9. The eutectic A28-1 according to claim 1 or 2, characterized in that, The eutectic A28-1 has a DSC pattern as shown in Figure 3.

10. A method for preparing eutectic A28-1 according to any one of claims 1-9, wherein the preparation method is selected from any one of the following methods: 1) Dissolve the eutectic of compound A and fumaric acid in N,N-dimethylformamide, trifluoroethanol or dimethyl sulfoxide, add water or an aqueous solvent to the solution, precipitate the solid, separate and dry it to obtain eutectic A28-1; Preferably, the eutectic of compound A and fumaric acid is a monofumaric acid eutectic of compound A; In some embodiments, the eutectic of compound A and fumaric acid is in form III; Preferably, the proportion of water in the aqueous solvent is arbitrary; Preferably, the aqueous solvent is an ether, alkane, or ester; Preferably, the ether is selected from any one of isopropyl ether, diethyl ether, or methyl tert-butyl ether, or a mixture thereof; the alkane is selected from any one of methane, n-heptane, or methylcyclohexane, or a mixture thereof; and the ester is selected from any one of ethyl acetate, methyl acetate, or butyl acetate, or a mixture thereof. Preferably, the addition of water or an aqueous solvent is accompanied by stirring; Preferably, the drying is vacuum drying, and the drying temperature is 30-60℃, preferably 40℃; 2) Compound A and fumaric acid were mixed and stirred in an aqueous alcohol solvent, a solid was precipitated, centrifuged and dried to obtain eutectic A28-1; Preferably, the alcohol solvent is selected from any one of ethanol, methanol, isopropanol, and n-propanol, or a mixture thereof; In some specific embodiments, the alcohol solvent is selected from ethanol; Preferably, the molar ratio of compound A to fumaric acid is 2:1 to 1:1; In some specific embodiments, the molar ratio of compound A to fumaric acid is 2:1; Preferably, the stirring time is ≥5 min, and the stirring temperature is 4℃-80℃; In some embodiments, the stirring time is 4 days and the stirring temperature is room temperature; Preferably, the drying temperature is 30℃-80℃, more preferably 40℃.

11. A pharmaceutical composition comprising a therapeutically effective amount of the eutectic A28-1 according to any one of claims 1-9, and at least one pharmaceutically acceptable carrier.

12. A formulation prepared from the pharmaceutical composition of claim 11, characterized in that, The formulation is selected from oral and parenteral formulations; Preferably, the formulation is an oral formulation; Preferably, the formulation is in the form of tablets, capsules, or suspension; Preferably, the formulation is in the form of capsules.

13. Use of the eutectic A28-1 of any one of claims 1-9, or the pharmaceutical composition of claim 10, or the formulation of claim 11 in the preparation of a medicament for the treatment or prevention of allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving chondrodysplasia, congenital chondrodysplasia, and / or diseases associated with excessive secretion of IFNα, IL12, and / or IL23; Preferably, the diseases associated with excessive secretion of IFNα, IL12 and / or IL23 are systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, multiple sclerosis and / or Crohn's disease.

14. A method for treating or preventing allergic diseases, inflammatory diseases, metabolic diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, transplant rejection, diseases involving chondrodysplasia, congenital chondrodysplasia, and / or diseases associated with excessive secretion of IFNα, IL12, and / or IL23, comprising administering to a patient a therapeutically effective amount of the cocrystal A28-1 as described in any one of claims 1-9, the pharmaceutical composition as described in claim 10, or the formulation as described in claim 11; Preferably, the diseases associated with excessive secretion of IFNα, IL12 and / or IL23 are systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, polymyositis, Sjögren's syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, multiple sclerosis and / or Crohn's disease.

15. The combined use of the eutectic A28-1 according to any one of claims 1-9, the pharmaceutical composition according to claim 11, or the formulation according to claim 12 with other pharmaceutical products.

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