Glucosamine derivative-containing composition, and preparation method therefor and use thereof

Abstract

A glucosamine derivative-containing composition comprising, based on the total weight of the composition, 55-70 wt%, preferably 55-65 wt%, more preferably 60-65 wt% of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. The present invention further relates to a use of the glucosamine derivative-containing composition in the preparation of a drug for preventing or treating bone or joint diseases of subjects in need.

Description

Compositions containing glucosamine derivatives, their preparation methods and uses

[0001] Cross-references to related applications

[0002] This disclosure is based on and claims priority to Chinese Patent Application No. 202410931495.3, filed on July 11, 2024, entitled “Compositions Containing Glucosamine Derivatives and Their Preparation Methods and Uses Thereof”, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This disclosure relates to compositions containing glucosamine derivatives, methods for their preparation and uses, and particularly to compositions containing 2-N-4,6-di-O-tributyryl-D-glucosamine, methods for their preparation and uses. Background Technology

[0004] Glucosamine, also known as glucosamine, is a compound formed by replacing one of the hydroxyl groups of glucose with an amino group. Glucosamine is an important precursor in the glycosylation of proteins and lipids and is one of the most abundant monosaccharides in nature. Typical glucosamine compounds include N-acetylglucosamine (GlcNAc) and N-butyrylglucosamine (GlcNBu). GlcNAc is a monomer of chitin and is considered to have anti-inflammatory, antitumor, and antioxidant effects, with wide applications in food, medicine, and cosmetics. Some studies have also shown that GlcNBu has therapeutic potential in bone and joint diseases.

[0005] Prodrug-based glucosamine derivatives have been developed to enhance or improve their efficacy in treating bone and joint diseases (such as osteoporosis and arthritis) by increasing bioavailability, stability, and reducing compound metabolism. Examples include compounds of formula (A) disclosed in patent documents CN109929001A and WO2019119117A1. Among these, N-butyryl-4,6-di-O-butyryl-D-glucosamine shows therapeutic effects in alleviating pain symptoms, cartilage degeneration, chondrocyte aggregation, and osteophyte formation in meniscectomy-induced osteoarthritis (OA) in rats.

[0006] Currently, the vast majority of patent applications related to glucosamine derivatives involve GlcNAc, such as WO2022161485A1, JP2023061032A, KR1020230001077A, JP2022000001A, US11110051B2, etc. On the one hand, in these patent applications, GlcNAc is mixed with other active ingredients to form compositions, and the vast majority of these are health products or beauty products, rather than pharmaceutical compositions. On the other hand, GlcNAc and GlcNBu prodrugs differ significantly in physicochemical properties and other aspects. Existing patent literature on GlcNAc-containing compositions offers no reference for the development of GlcNBu prodrugs (such as compounds of formula (A), especially N-butyryl-4,6-di-O-butyryl-D-glucosamine) compositions (especially pharmaceutical compositions). Summary of the Invention

[0007] The technical problem to be solved by this disclosure is a composition containing a glucosamine derivative, a method for preparing the composition, and its uses. Specifically, the glucosamine derivative is a prodrug of GlcNBu or a pharmaceutically acceptable salt thereof. In the compositions of this disclosure, the prodrug of GlcNBu, as the main active ingredient, exhibits excellent dissolution properties and excellent absorption in vivo. Furthermore, these compositions possess good stability and remain stable under long-term storage conditions, and can be used for the prevention and / or treatment of bone and / or joint diseases, such as osteoporosis and / or arthritis.

[0008] This disclosure provides a composition containing a glucosamine derivative comprising 55 wt% to 70 wt% of a prodrug of GlcNBu as shown in Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0009] R 2 It is hydrogen, acyl, or alkyl;

[0010] R 1 R 3 R 4 and R 5 Independently hydrogen, substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, alkylaryl, hydrocarbon group containing a carbide ring or heterocycle, or Q 1 C(O)-, amino acid residues (including natural and non-natural amino acid residues), peptide residues, phosphonyl group, sulfonyl group, amino group, condition R 1 R 3 R 4 and R 5 They are not both hydrogen;

[0011] Q 1The substituted or unsubstituted groups are selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, cycloalkyl, heterocycloalkyl, alkoxy, aryloxy, and arylalkoxy; optionally, Q 1 The -NH2 and -OH groups in the substance, if present, can further replace the protecting groups.

[0012] In some implementations, R 2 It is hydrogen.

[0013] In some implementations, Q 1 Selected from alkoxy, aryloxy, and arylalkoxy groups.

[0014] In some implementations, R 1 R 3 R 4 and R 5 One or more groups in the group can be independently selected from alkoxycarbonyl, aryloxycarbonyl and arylalkoxycarbonyl.

[0015] In some implementations, R 1 R 3 R 4 and R 5 Each is independently H, C1-C12 alkyl acyl, or α-amino acyl derived from natural amino acids.

[0016] In a preferred embodiment, R 1 For H, and R 3 R 4 and R 5 Each can be independently selected from the group consisting of H, C1-C6 alkyl acyl groups, and α-amino acyl groups derived from glycine, alanine, valine, leucine, isoleucine, and phenylalanine, provided that R... 3 R 4 and R 5 The α-aminoacyl group is not simultaneously H. Specifically, the C1-C6 alkylacyl group may be selected from formyl, acetyl, propionyl, n-butyryl, isobutyryl, n-valeryl, 2-methylbutyryl, 3-methylbutyryl, tert-butylformyl, n-hexanoyl, 2-methylvaleryl, 3-methylvaleryl, 4-methylvaleryl, tert-butylacetyl, 2,3-dimethylbutyryl, and 2,2-dimethylbutyryl; preferably selected from formyl, acetyl, propionyl, n-butyryl, or isobutyryl; more preferably acetyl or n-butyryl. The preferred α-aminoacyl group is an α-aminoacyl group derived from alanine and valine, more preferably an α-aminoacyl group derived from valine.

[0017] In a more preferred embodiment, R 1 and R 3 Both are H, and R4 and R 5 Each can be independently selected from the group consisting of H, C1-C6 alkyl acyl groups, and α-amino acyl groups derived from glycine, alanine, valine, leucine, isoleucine, and phenylalanine, provided that R... 4 and R 5 The C1-C6 alkyl acyl group may be acetyl, propionyl, n-butyryl, isobutyryl, n-valeryl, 2-methylbutyryl, 3-methylbutyryl, tert-butylformyl, or n-hexanoyl. Acetyl and n-butyryl are most preferred. The preferred α-amino acyl group is derived from alanine and valine, and most preferably from valine.

[0018] In some embodiments, the compound according to formula (I) is an α-terminal isomer; in another embodiment, the compound according to formula (I) is a β-terminal isomer; and in yet another embodiment, the compound according to formula (I) is a mixture of α- and β-terminal isomers.

[0019] In some embodiments, the compound of formula (I) is selected from the compounds shown in Table 1 or their pharmaceutically acceptable salts.

[0020] Table 1

[0021] In some embodiments of this disclosure, the composition comprises 55 wt% to 70 wt% of compound 1 or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients. In some such embodiments, the content of compound 1 is 55 wt% to 70 wt%, 55 wt% to 65 wt%, or 60 wt% to 65 wt%, for example 61 wt%, 61.5 wt%, 62 wt%, 62.5 wt%, 63 wt%, 63.5 wt%, or 64 wt%. In this disclosure, higher levels of the active ingredient are advantageous for controlling the size and / or dimensions of the composition (e.g., tablets or capsules) within a smaller range, which can reduce the frequency of administration or alleviate swallowing difficulties when the composition is administered in high doses. In some embodiments, in the compositions of this application, the D90 particle size of compound 1 or a pharmaceutically acceptable salt thereof is 150 μm or more (or 200 μm or more, 300 μm or more, 400 μm or more), preferably 150 μm-500 μm (e.g., about 300 μm), more preferably 200 μm-400 μm. In some embodiments, the D50 particle size of compound 1 or a pharmaceutically acceptable salt thereof is 30 μm or more, preferably 30 μm-100 μm. In some embodiments, the D10 particle size of compound 1 or a pharmaceutically acceptable salt thereof is 4 μm or more, preferably 10 μm-50 μm, more preferably 15 μm-20 μm. In some such embodiments, the D90 particle size of compound 1 or a pharmaceutically acceptable salt thereof is 150 μm-500 μm, the D50 particle size is 30 μm-100 μm, and the D10 particle size is 10 μm-50 μm. Controlling the particle size of compound 1 or its salts can improve the continuity of the production process while ensuring the uniformity of product content.

[0022] In some embodiments, the pharmaceutically acceptable excipients include, but are not limited to, one or more of fillers (or diluents), disintegrants, flow aids, lubricants, and surfactants. In some embodiments, the pharmaceutically acceptable excipients include fillers, disintegrants, flow aids, and lubricants. In some embodiments, the pharmaceutically acceptable excipients include fillers, disintegrants, flow aids, lubricants, and surfactants. In some embodiments, the pharmaceutically acceptable excipients are fillers, disintegrants, flow aids, and lubricants. In some embodiments, the pharmaceutically acceptable excipients further include coating materials.

[0023] In some embodiments, the filler includes, but is not limited to, one or more of microcrystalline cellulose, lactose, starch, mannitol, and calcium dihydrogen phosphate, sorbitol, xylitol, and magnesium carbonate. In some embodiments, the filler is lactose and / or microcrystalline cellulose. In some embodiments, the filler content is 5 wt%-30 wt%, preferably 5 wt%-25 wt%, more preferably 10 wt%-22.5 wt%, for example 10.5 wt%, 11 wt%, 11.5 wt%, 12 wt%, 12.5 wt%, 13 wt%, 14 wt%, 15 wt%, 15.5 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, or 22 wt%. In some embodiments, the filler is microcrystalline cellulose and lactose, wherein the microcrystalline cellulose content is 2 wt%-7 wt% (e.g., 5 wt%) and the lactose content is 5 wt%-20 wt% (e.g., 6.5 wt%, 7.5 wt%, 10.5 wt%, or 17.5 wt%). In some embodiments, the filler is microcrystalline cellulose and mannitol, wherein the microcrystalline cellulose content is 2 wt%-7 wt% (e.g., 5 wt%) and the mannitol content is 3 wt%-8 wt% (e.g., 5.5 wt%).

[0024] In some embodiments, the disintegrant includes, but is not limited to, microcrystalline cellulose, sodium carboxymethyl starch, croscarmellose sodium, croscarmellose calcium, croscarmellose polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, croscarmellose alginate, sodium alginate, potassium alginate, gellan gum, pregelatinized starch, corn starch, carboxymethyl cellulose, glycine, and any combination thereof. In some embodiments, the disintegrant is sodium carboxymethyl starch. In some embodiments, the content of the disintegrant is 10 wt%-30 wt%. In some embodiments, the disintegrant is sodium carboxymethyl starch, and the content of sodium carboxymethyl starch is 15 wt%-25%.

[0025] In some embodiments, the flow aid includes, but is not limited to, colloidal silica (such as anhydrous colloidal silica), talc, magnesium trisilicate, powdered cellulose, starch, and any combination thereof. In some embodiments, the content of the flow aid is 1 wt%-3 wt%. In some embodiments, the flow aid is colloidal silica, and the content of the colloidal silica is 1 wt%-3 wt%, or 1.5 wt%-2.5 wt%, for example, 2 wt%.

[0026] In some embodiments, the lubricant includes, but is not limited to, magnesium stearate, stearic acid, calcium stearate, aluminum stearate, zinc stearate, sodium stearoyl fumarate, hydrogenated castor oil, PEG 4000-8000, talc, glyceryl monostearate, glyceryl dibehenate (e.g., commercially available from Gattefossé, trade name 888ATO), and glyceryl palmitate stearate (e.g., commercially available from Gattefossé, trade name...). Hydrogenated cottonseed oil, castor oil, and any combination thereof. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the lubricant content is 1 wt%-6 wt%, for example 2 wt%, 3 wt%, 4 wt%, or 5 wt%. In some embodiments, the lubricant is magnesium stearate, and the magnesium stearate content is 2 wt%-5 wt%, for example 3 wt%.

[0027] In some embodiments, the surfactant includes, but is not limited to, sodium dodecyl sulfate, poloxamer, stearic acid, povidone, and any combination thereof. In some embodiments, the surfactant content is 0.5 wt% to 2 wt%, for example, 1 wt%.

[0028] In some embodiments, the composition further comprises a coating material. The coating material may be a conventional immediate-release coating premix in the art. In some embodiments, the content of the coating material is 2 wt% to 5 wt% of the total weight of the composition excluding the coating material, for example, about 3 wt%.

[0029] In some embodiments, the composition comprises 50 wt%-70 wt% of compound 1 or a pharmaceutically acceptable salt thereof, 5 wt%-30 wt% of a filler, 10 wt%-30 wt% of a disintegrant, 1 wt%-3 wt% of a flow aid, 1 wt%-6 wt% of a lubricant, and 0 wt%-2 wt% of a surfactant, optionally further comprising a coating material. In some such embodiments, the D90 particle size of compound 1 or a pharmaceutically acceptable salt thereof is greater than 100 μm, preferably between 100 μm and 500 μm. The preferred types of each pharmaceutically acceptable excipient are as described above.

[0030] In some preferred embodiments, the composition comprises 50 wt%-70 wt% of compound 1, 2 wt%-7 wt% of microcrystalline cellulose, 5 wt%-20 wt% of lactose, 10 wt%-25 wt% of sodium carboxymethyl starch, 1 wt%-3 wt% of colloidal silica, 2 wt%-6 wt% of magnesium stearate and 0 wt%-2 wt% of sodium dodecyl sulfate, and the D90 particle size of compound 1 is greater than 100 μm.

[0031] In some preferred embodiments, the composition comprises 60wt%-65wt% of compound 1, 2wt%-7wt% of microcrystalline cellulose, 5wt%-20wt% of lactose, 10wt%-25wt% of sodium carboxymethyl starch, 1.5wt%-2.5wt% of colloidal silica, 3wt%-5wt% of magnesium stearate and 0wt%-2wt% of sodium dodecyl sulfate, and the D90 particle size of compound 1 is 100μm-500μm.

[0032] In some preferred embodiments, the composition comprises 55wt%-70wt% of compound 1, 2wt%-7wt% of microcrystalline cellulose, 3wt%-8wt% of mannitol, 10wt%-25wt% of sodium carboxymethyl starch, 1.5wt%-2.5wt% of colloidal silica, 2wt%-6wt% of magnesium stearate and 0wt%-2wt% of sodium dodecyl sulfate, and the D90 particle size of compound 1 is 100μm-500μm.

[0033] In some embodiments, the composition contains 50 mg to 1000 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, as a free base (e.g., 100 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 750 mg, 800 mg, 900 mg), preferably 100 mg to 500 mg.

[0034] In some embodiments, the composition is in the form of a unit formulation and contains 50 mg to 1000 mg (e.g., 100 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 750 mg, 800 mg, 900 mg), preferably 100 mg to 500 mg, of a compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as free base.

[0035] In some embodiments, when the dissolution of the composition is tested according to Method II of Dissolution and Release Determination in Appendix 0931 of the 2020 edition of the Chinese Pharmacopoeia, the cumulative dissolution amount of the drug composition within 30 minutes reaches or exceeds 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% of the labeled amount; the determination conditions of Method II of Dissolution Determination are a rotation speed of 50 rpm, a water bath temperature of 37 ± 0.5 °C, and a dissolution medium of 900 mL. In some such embodiments, the dissolution medium is a pH 4.5 acetate buffer solution.

[0036] In some embodiments, the composition, when stored at 40°C and 75% RH for 6 months, exhibits an increase in total impurities of less than 2%, 1.5%, 1.0%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% by weight. In some embodiments, the composition, when stored at 25°C and 60% RH for 2 years, exhibits an increase in total impurities of less than 2%, 1.5%, 1.0%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% by weight. The composition demonstrates good stability during long-term storage.

[0037] In some embodiments, the composition is a solid dosage form. The solid dosage form includes, but is not limited to, capsules, pills, tablets, powders, granules, pellets, lozenges, or sugar-coated pills.

[0038] In some embodiments, the composition is prepared by a dry process. The dry process includes, but is not limited to, dry granulation or direct powder compression. In some embodiments, the composition is prepared by a dry granulation process. In some embodiments, the composition is not prepared by a wet process or melt extrusion.

[0039] In some embodiments, the composition includes an intraparticle component and an extraparticle component;

[0040] The intraparticle components include 50wt%-70wt% of compound 1 or a pharmaceutically acceptable salt thereof, 5wt%-30wt% of filler, 7wt%-12.5wt% of disintegrant, 1wt%-2.5wt% of lubricant and 0wt%-2wt% of surfactant, and the D90 particle size of compound 1 is greater than 100μm.

[0041] The extraparticle components include 3wt%-12.5wt% of a disintegrant, 1wt%-3wt% of a flow aid, and 1wt%-3.5wt% of a lubricant;

[0042] And optional coating materials. Among them, the preferred types of pharmaceutically acceptable excipients are as described above.

[0043] In some embodiments, the intraparticle components include 50wt%-70wt% of Compound 1, 2wt%-7wt% of microcrystalline cellulose, 5wt%-20wt% of lactose, 7wt%-12.5wt% of sodium carboxymethyl starch, 1wt%-3wt% of colloidal silica, 1wt%-2.5wt% of magnesium stearate, and 0wt%-2wt% of sodium dodecyl sulfate, and the D90 particle size of Compound 1 is 100μm-500μm.

[0044] In some embodiments, the intraparticle components include 50wt%-70wt% of Compound 1, 2wt%-7wt% of microcrystalline cellulose, 3wt%-8wt% of mannitol, 7wt%-12.5wt% of sodium carboxymethyl starch, 1wt%-3wt% of colloidal silica, 1wt%-2.5wt% of magnesium stearate, and 0wt%-2wt% of sodium dodecyl sulfate, and the D90 particle size of Compound 1 is 100μm-500μm.

[0045] In some embodiments, the extraparticle components include 3 wt%-12.5 wt% sodium carboxymethyl starch, 1 wt%-3 wt% colloidal silica, and 1 wt%-3.5 wt% magnesium stearate.

[0046] In another aspect of this disclosure, a method for preparing the composition is provided, including but not limited to dry granulation and direct powder compression processes.

[0047] In some embodiments, the composition is prepared by a dry granulation process, the preparation method of which includes the following steps:

[0048] 1a) The compound of formula (I) or a pharmaceutically acceptable salt thereof, the filler, the disintegrant of the granule component, the lubricant of the granule component and the surfactant (if any) are mixed evenly, and then dry granulated, and sieved to obtain dry granules.

[0049] 1b) Mix the dry granules, the disintegrant of the extragranule components, the glidant, and the lubricant of the extragranule components evenly, and compress into tablets;

[0050] 1c) Optionally, the tablets are coated with the coating material.

[0051] In some embodiments, the composition is prepared by a dry granulation process, the preparation method of which includes the following steps:

[0052] 2a) The compound of formula (I) or a pharmaceutically acceptable salt thereof, the filler, the disintegrant of the granule component, the lubricant of the granule component and the surfactant (if any) are mixed evenly, and then dry granulated, and sieved to obtain dry granules;

[0053] 2b) Mix the dry granules, the disintegrant of the extragranule components, the flow aid, and the lubricant of the extragranule components evenly, and then fill the capsules.

[0054] In some embodiments, the composition is prepared by a powder direct pressing process, the preparation method of which includes the following steps:

[0055] The compound of formula (I) or a pharmaceutically acceptable salt thereof, the filler, the disintegrant, the glidant, and the surfactant (if any) are mixed evenly, and then mixed evenly with the lubricant, and then compressed into tablets or capsules.

[0056] In another aspect of this disclosure, a method for preparing the composition containing the glucosamine derivative is also provided, wherein the preparation method is any one of method 1, method 2 or method 3 described below;

[0057] Method 1:

[0058] 1a) The compound of formula (I) or a pharmaceutically acceptable salt thereof, the filler, the disintegrant of the granule component, the lubricant of the granule component and the surfactant (if any) are mixed evenly, and then dry granulated, and sieved to obtain dry granules.

[0059] 1b) Mix the dry granules, the disintegrant of the extragranule components, the glidant, and the lubricant of the extragranule components evenly, and compress into tablets;

[0060] 1c) Optionally, the tablets are coated with the coating material;

[0061] Method 2:

[0062] 2a) The compound of formula (I) or a pharmaceutically acceptable salt thereof, the filler, the disintegrant of the granule component, the lubricant of the granule component and the surfactant (if any) are mixed evenly, and then dry granulated, and sieved to obtain dry granules;

[0063] 2b) Mix the dry granules, the disintegrant of the extragranule components, the flow aid, and the lubricant of the extragranule components evenly, and then fill the capsules;

[0064] Method 3:

[0065] The compound of formula (I) or a pharmaceutically acceptable salt thereof, the filler, the disintegrant, the glidant, and the surfactant (if any) are mixed evenly, and then mixed evenly with the lubricant, and then compressed into tablets or capsules.

[0066] The preferred types and amounts of the compound of formula (I) and each pharmaceutically acceptable excipient are as described above.

[0067] In accordance with common knowledge in the art, the dry granulation process and the direct powder pressing process may optionally include crushing and sieving operations in order to control the uniformity and flowability of the powder.

[0068] In step 1c), the coating operation can be performed in accordance with conventional methods and conditions in the art. Typically, the coating material is prepared as a coating solution for the coating operation. In some embodiments, the coating material is prepared as a 10 wt% coating solution for coating. In some embodiments, the coating temperature is 40°C-50°C.

[0069] In this disclosure, the preparation method is generally carried out at room temperature.

[0070] In another aspect of this disclosure, the use of the glucosamine derivative-containing composition in the preparation of a medicament for the prevention or treatment of bone or joint diseases in a subject in need is also provided, or the use of the glucosamine derivative-containing composition in the preparation of a health supplement for the prevention of bone or joint diseases, or the use of the glucosamine derivative-containing composition in the preparation of an additive for the prevention of bone or joint diseases is also provided.

[0071] In some embodiments, the bone or joint disease is osteoporosis, osteopenia, and / or arthritis. In some embodiments, the arthritis is osteoarthritis, inflammatory arthritis (including rheumatoid arthritis or psoriatic arthritis), traumatic arthritis, degenerative arthritis, or developmental dysplastic arthritis.

[0072] In some embodiments, the desired subject is a mammal. In some embodiments, the desired subject is a human. In some embodiments, the desired subject is a non-human primate, such as a dog, cat, horse, cow, sheep, pig, monkey, etc.

[0073] It should be understood that, within the scope of this disclosure, the above-described technical features and the technical features specifically described below (such as in the detailed embodiments) can be combined with each other to form new or preferred technical solutions. These will not be elaborated upon here.

[0074] The positive and progressive effects of this disclosure are as follows:

[0075] 1) The glucosamine derivative-containing composition disclosed herein can be used as a drug for the prevention or treatment of joint and bone diseases in mammals, such as arthritis and osteoporosis, and can simultaneously meet the requirements of clinical use, patient compliance, and industrial-scale production.

[0076] 2) The glucosamine derivative-containing compositions disclosed herein exhibit excellent solubility, remain stable even under long-term storage conditions, show low growth of related substances, and achieve a relatively long half-life, which is beneficial for the prevention and treatment of related diseases.

[0077] 3) The preparation method disclosed herein can produce compositions containing glucosamine derivatives with good chemical stability, and the preparation method can meet the requirements of industrial-scale production. Detailed Implementation

[0078] To provide a clear and consistent understanding of the terminology used in this disclosure, some definitions are provided below. Furthermore, unless otherwise specified, all technical and scientific terms used in this disclosure have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0079] When used in conjunction with the term "comprising" in the claims and / or description, the word "a" can mean "one," but it also aligns with the meanings of "one or more," "at least one," and "one or more." Similarly, the word "another" can mean at least a second or more.

[0080] As used in this specification and claims, the words “comprising” (and any form of inclusion, such as “comprising” and “including”), “having” (and any form of having, “having”, “including” and “containing”) are inclusive and open-ended and do not exclude additional unlisted elements or processing steps.

[0081] The terms “about,” “approximately,” or “around” are used to indicate that the value includes errors introduced by the instruments and methods used in determining the value, and generally means a deviation of 10% or less from the given value, especially 5% or less, and even more especially 2% or less.

[0082] As used in this disclosure, the term "derivative" should be understood as another compound that is structurally similar but differs in some fine structures.

[0083] This specification involves many chemical terms and abbreviations used by those skilled in the art. However, for clarity and consistency, definitions of selected terms are provided.

[0084] As used in this disclosure, the term "alkyl" (unless otherwise stated) refers to a saturated hydrocarbon having 1 to 18 carbon atoms, including straight-chain, branched, and cyclic alkyl groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, isopropyl, tert-butyl, sec-butyl, isobutyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. The term "alkyl" includes unsubstituted alkyl groups and substituted alkyl groups. The term "C1-C" n Alkyl (where n is an integer from 2 to 12) refers to an alkyl group having 1 to n carbon atoms. Alkyl residues may be substituted or unsubstituted. In some embodiments, for example, alkyl groups may be substituted with groups such as hydroxyl, amino, carboxyl, carboxylic acid ester, amide, carbamate, aminoalkyl, etc.

[0085] As used in this disclosure, the term "alkenyl" (unless otherwise stated) refers to an unsaturated hydrocarbon having 2 to 18 carbon atoms, including straight-chain, branched, and cyclic non-aromatic alkenyl groups, and containing one to six carbon-carbon double bonds. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propen-2-yl, 1-buten-3-yl, 1-buten-4-yl, 2-buten-4-yl, 1-penten-5-yl-1,3-pentadien-5-yl, cyclopentenyl, cyclohexenyl, ethylcyclopentenyl, ethylcyclohexenyl, etc. The term alkenyl includes both unsubstituted and substituted alkenyl groups. The term "C2-C" is also used. n "Alkenyl", where n is an integer from 3 to 18, refers to an alkenyl group having 2 to "n" carbon atoms.

[0086] As used in this disclosure, the term "alkynyl" (unless otherwise stated) refers to an unsaturated hydrocarbon having 2 to 18 carbon atoms, including straight-chain, branched, and cyclic non-aromatic alkynyl groups, and containing one to six carbon-carbon triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propyn-3-yl, 1-butyn-4-yl, 2-butyn-4-yl, 1-pentyn-5-yl, 1,3-pentadiyn-5-yl, etc. The term alkynyl includes both unsubstituted and substituted alkynyl groups. The term "C2-C" is also used. n "Alkyne", where n is an integer from 3 to 18, refers to an alkynyl group having 2 to "n" carbon atoms.

[0087] As used in this disclosure, the terms "carbocyclic ring" and equivalent groups (unless otherwise stated) refer to 3- to 15-membered carbocyclic systems of monocyclic, spirocyclic (with rings sharing an atom), or fused (with rings sharing at least one bond) rings, whether saturated or partially unsaturated.

[0088] As used in this disclosure, the term "cycloalkyl" refers to a saturated group, including both unsubstituted and substituted cycloalkyl groups. The term "C3-C" is also used. n "Cycloalkyl", where n is an integer from 4 to 15, refers to a cycloalkyl group having 3 to "n" carbon atoms in a ring structure. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopenten-1-yl, cyclopenten-2-yl, cyclopenten-3-yl, cyclohexyl, cyclohexen-1-yl, cyclohexen-2-yl, cyclohexen-3-cycloheptyl, bicyclo[4,3,0]nonyl, norbornyl, etc. "Cycloalkyl" can be... Monocyclic or polycyclic. Monocyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, or cyclotetradecyl. Examples of bicyclic alkyl groups are norbornene, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.1]octane. Examples of substituted cycloalkyl groups are 4-methylcyclohexyl and 2,3-dimethylcyclopentyl.

[0089] As used in this disclosure, the terms "heterocyclic alkyl" and equivalent groups (unless otherwise stated) refer to cyclic systems containing one or more heteroatoms (such as nitrogen, oxygen, sulfur, or phosphorus atoms) in a monocyclic, spirocyclic (sharing an atom between rings), or fused-ring (sharing at least one bond between rings) system, the number of which can be 1 to 6. Heteroatoms can be atoms themselves or can be substituted (e.g., NH, NRx (Rx being alkyl, acyl, aryl, heterocyclic aryl, or cycloalkyl), PO2, SO, SO2, or related forms). Heterocycles can be three- to fifteen-membered rings. Heterocyclic alkyl groups can be connected to a carbon atom or to a heteroatom (e.g., via a nitrogen atom). Examples of heterocyclic alkyl groups include, but are not limited to, pyrrolyl, tetrahydrofuranyl, tetrahydrodithienyl, tetrahydropyranyl, tetrahydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, thiaoxyl, piperazine, azirrocyclobutane, oxacyclobutane, thioheterocyclobutane, high-piperidinyl, oxacycloheptane, 1,2,3,6-tetrahydropyridinyl, 2-pyrrololinyl, 3-pyrrololinyl, dihydroindolyl, 2H-pyranyl, 4H-pyranyl, dialkyl, 1,3-dioxolanecyclo, pyrazolinyl, dithiaalkyl, dithiacyclopentane, dihydropyranyl, dihydrothiaphenyl, dihydrofuranyl, pyrazolyl, imidazolinyl, imidazolinyl, 3-azabicyclo[3,1,0]hexyl, 3-azabicyclo[4,1,0]heptyl, 3H-indolyl, quinazinyl, and sugars, etc. The term heterocyclic alkyl includes both unsubstituted and substituted heterocyclic alkyl groups. The term "C3-C" is also used. n "Heterocyclic alkyl", where n is an integer from 4 to 15, refers to a heterocyclic alkyl group having 3 to the number of atoms shown in the "n" in a cyclic structure, including at least one heterogroup or atom as defined above.

[0090] As used in this disclosure, the terms "aryl" and "aromatic ring" refer to an aromatic group having "4n+2" (π) electrons and 6 to 14 ring atoms in a conjugated monocyclic or polycyclic system, where n is an integer from 1 to 3. A polycyclic system includes at least one aromatic ring. Unless otherwise stated, aryl groups may be directly linked or linked via C1-C3 alkyl groups (also called "aralkyl"). Examples of aryl groups include, but are not limited to, phenyl, benzyl, phenethyl, 1-phenylethyl, tolyl, naphthyl, biphenyl, terphenyl, indenyl, benzocyclooctenyl, benzocycloheptenyl, azulel, acenaphthel, fluorenyl, phenanthrene, anthracene, etc. The term "aryl" includes unsubstituted aryl and substituted aryl groups, examples of which include, but are not limited to, alkyl-substituted aryl groups (also called "alkylaryl"). The term "C5-C"... n An aryl group (where n is an integer from 6 to 15) is an aryl group having 6 to the number of carbon atoms indicated by “n” in a ring structure, including at least one heterocyclic group or atom as defined above.

[0091] As used in this disclosure, the terms "heteroaryl" and "heteroary ring" refer to an aromatic group having "4n+2" (π) electrons in a conjugated monocyclic or polycyclic system, unless otherwise specified, where n is an integer from 1 to 3, and includes one to six heteroatoms (e.g., N, O, S, P) or includes heteroatom groups (e.g., NH, NRx (Rx is alkyl, acyl, aryl, heteroaryl, or cycloalkyl), PO2, SO, SO2, etc.). Polycyclic systems include at least one heteroaryl ring. Unless otherwise specified, heteroaryl groups may be directly attached or linked via C1-C3 alkyl groups (also referred to as "heteroarylalkyl" or "heteroarylalkyl"). Heteroaryl groups may be attached to a carbon atom or to a heteroatom (e.g., via a nitrogen atom). Examples of heteroaryl groups include, but are not limited to, pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thiophene; isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolidinyl, quinolinyl, isoquinolinyl, indoleyl, isoyndoleyl, chromenyl, isocherenyl, benzimidazolyl, benzofuranyl, cenolinyl, indazoleyl, inazinyl, phthalazinyl, pyridazinyl, pyridazinyl, and others. Azinyl, triazinyl, isoindolyl, pteridinyl, furanyl, benzofuranyl, benzothiazolyl, benzothiopheneyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinolinyl, quinolinoneyl, isoquinolinoneyl, quinoxalinyl, naphthidyl, furan-pyridyl, carbazoleyl, phenanthridineyl, acridineyl, peryleneyl, phenanthrolinel, phenazinyl, phenothiazinyl, phenotoxazinyl, dibenzofuranyl, etc. The term "heteroaryl" includes both unsubstituted and substituted heteroaryl groups. The term "C5-C"... 15 "Heteroaryl", where n is an integer from 6 to 15, refers to a heteroaryl group having from 5 to the number of atoms shown in the "n" in the ring structure, including at least one heterocyclic group or atom as defined above.

[0092] As used in this disclosure, the term "heterocyclic" or "heterocyclic" includes heterocyclic alkyl and heterocyclic aryl groups. Examples of heterocycles include, but are not limited to, acridine, acridine, benzimidazolyl, benzofuranyl, benzothiophene, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzoisoxazolyl, benzoisothiazolyl, 4αH-carbazolyl, carbaolinyl, benzodihydropyranyl, chromenyl, cenyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofurano[2,3-b]tetrahydrofuran, and furan. Furazanyl, imidazoalkyl, imidazolinyl, imidazolyl, 1H-indazole, dihydroindolyl, 3H-indolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthidyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolyl, oxazolylalkyl, pyrimidinyl, phenanthridine, phenanthroxorline yl, phenazinyl, phenothiazinyl, phenotoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidinoneyl, 4-piperidinoneyl, piperinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolylalkyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridoxazazole, pyridoimidazole, pyridothiazazole, pyridinyl, pyrroleyl, quinazolinyl, quinolinyl, 4H-quinazinyl, quinoxalinyl, quininecycloyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolineyl Phosphoryl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thiaanthryl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthonyl, etc. The term "heterocyclic" includes both unsubstituted and substituted heterocyclic groups.

[0093] As used in this disclosure, the terms "amine" or "amino" refer to unsubstituted or substituted amino groups of the general formula -NR. a R b The fragment, in which R a and R b Each is independently hydrogen, alkyl, aryl, or heterocyclic, or R a and R bTogether with the nitrogen atom to which they are attached, they form a heterocycle. The term amino refers to a compound or fragment in which at least one carbon or heteroatom is covalently bonded to a nitrogen atom. Therefore, as used in this disclosure, the terms "alkylamino" and "dialkylamino" refer to amino groups having one and at least two C1-C6 alkyl groups respectively attached to a nitrogen atom. The terms "arylamino" and "diarylamino" include groups with at least one or two aryl groups attached to a nitrogen atom. The terms "amide" or "aminocarbonyl" refer to a structure in which the carbonyl or thiocarbonyl group of a compound or fragment is attached to a nitrogen atom. The term "acylamino" refers to a structure in which an amino group is directly attached to an acyl group.

[0094] As used in this disclosure, the term "nitro" refers to -NO2. The terms "halogenated" and "halogen" refer to substituents of bromine, chlorine, fluorine, or iodine. The terms "thiol," "thio," or "mercapto" refer to -SH. The term "hydroxyl" or "hydroxyl group" refers to -OH. The term "alkathio" refers to a structure in which an alkyl group is attached to a mercapto group. Suitable alkathio groups include groups having 1 to about 12 carbon atoms (optimally 1 to about 6 carbon atoms). As used in this disclosure, the term "alkylcarboxyl" refers to a structure in which an alkyl group is attached to a carboxyl group.

[0095] As used in this disclosure, the term "alkoxy" or "lower alkoxy" refers to a structure in which an alkyl group is bonded to an oxygen atom. Representative alkoxy groups include those having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, tert-butoxy, etc. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, butoxy, pentoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, etc. The term alkoxy includes unsubstituted or substituted alkoxy groups, as well as perhaloalkoxy groups.

[0096] As used in this disclosure, the terms "carbonyl" or "carboxyl" include structures in compounds and segments in which carbon atoms are connected to oxygen atoms by double bonds. Examples of carbonyl moieties include aldehydes, ketones, carboxylic acids, amides, esters, acid anhydrides, etc. The term "ester" refers to a compound that can be represented by the general formula RCOOR' (carboxylic acid ester, where R and R' are independently selected from C1-C6 alkyl groups, such as methyl, ethyl, propyl, etc., but not limited thereto) or the general formula RSO3R' (sulfonate ester, where R and R' are independently selected from C1-C6 alkyl groups, such as methyl, ethyl, propyl, etc., but not limited thereto), and is generally given by reacting a carboxylic acid or a sulfonic acid with an alcohol (eliminating a molar of water).

[0097] As used in this disclosure, the term "acyl" refers to a structure in which a carbonyl group is attached to a hydrogen atom (i.e., a formyl group), an aliphatic group (C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, such as an acetyl group), a cycloalkyl group (C3-C8 cycloalkyl), a heterocyclic group (C3-C8 heterocyclic alkyl and C5-C6 heteroaryl), or an aryl group (C6 aryl, such as benzoyl). The acyl group can be unsubstituted or substituted (e.g., salicylyl).

[0098] As used in this disclosure, the term "amino acid" generally refers to an organic compound that contains both a carboxylic acid group and an amino group. The term "amino acid" includes both "natural" and "non-natural" amino acids. Additionally, the term "amino acid" includes O-alkylated and N-alkylated amino acids, as well as amino acids having nitrogen, sulfur, or oxygen-containing side chains (e.g., Lys, Cys, or Ser), wherein the nitrogen, sulfur, or oxygen atoms may or may not be acylated or alkylated. Amino acids can be L-amino acids, D-amino acids, or a mixture of L- and D-amino acids, including (but not limited to) racemic mixtures.

[0099] As used in this disclosure, the term "natural amino acid" and its equivalents refer to L-amino acids or non-protein-forming amino acids that are commonly found in naturally occurring proteins. Examples of natural amino acids include, but are not limited to, alanine (Ala), cysteine ​​(Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Lys), leucine (Leu), methionine (Met), asparagine (Asn), proline (Pro), glutamine (Gln), arginine (Arg), serine (Ser), threonine (Thr), tryptophan (Trp), tyrosine (Tyr), β-alanine (β-Ala), γ-aminobutyric acid (GABA), and 4-hydroxy-L-isoleucine, etc.

[0100] As used in this disclosure, the term "non-natural amino acid" refers to any derivative of a natural amino acid, including D-type amino acids and their derivatives, as well as α- and β-amino acid derivatives. It should be noted that some non-natural amino acids (e.g., hydroxyproline) used in this disclosure may exist naturally in certain biological tissues or specific proteins. Amino acids with many different protecting groups suitable for direct application in solid-phase peptide synthesis are readily available. In addition to the twenty most common natural amino acids, non-natural amino acids and amino acid derivatives (common abbreviations in parentheses) may be used according to this disclosure, including: 2-aminoadipic acid (Aad), 3-aminoadipic acid (β-Aad), 2-aminobutyric acid (2-Abu), α,β-dehydro-2-aminobutyric acid (8-AU), 1-aminocyclopropane-1-carboxylic acid (ACPC), aminoisobutyric acid (Aib), 3-aminoisobutyric acid (β-Aib), 2-amino-thiazoline-4- Carboxylic acids, 5-aminovaleric acid (5-Ava), 6-aminohexanoic acid (6-Ahx), 2-aminoheptanoic acid (Ahe), 8-aminooctanoic acid (8-Aoc), 11-aminoundecanoic acid (11-Aun), 12-aminododecanoic acid (12-Ado), 2-aminobenzoic acid (2-Abz), 3-aminobenzoic acid (3-Abz), 4-aminobenzoic acid (4-Abz), 4-amino-3-hydroxy-6-methylheptanoic acid (Statine, Sta), aminooxyethyl Acids (Aoa), 2-aminotetrahydronaphthalene-2-carboxylic acid (ATC), 4-amino-5-cyclohexyl-3-hydroxyvalerate (ACHPA), p-aminophenylalanine (4-NH2-Phe), 2-aminopimelic acid (Apm), biphenylalanine (Bip), p-bromophenylalanine (4-Br-Phe), o-chlorophenylalanine (2-Cl-Phe), m-chlorophenylalanine (3-Cl-Phe), p-chlorophenylalanine (3-Cl-Phe), m-chlorotyrosine (3- Cl-Tyr), p-benzoylphenylalanine (Bpa), tert-butylglycine (TLG), cyclohexylalanine (Cha), cyclohexylglycine (Chg), desmodium (Des), 2,2-diaminopimelic acid (Dpm), 2,3-diaminopropionic acid (Dpr), 2,4-diaminobutyric acid (Dbu), 3,4-dichlorophenylalanine (3,4-Cl2-Phe), 3,4-difluorophenylalanine (3,4-F2-Phe), 3,5-diiodotyrosine (3,5-I2-Tyr), N-ethylglycine (EtGly), N-ethylasparagine (EtAsn), o-fluorophenylalanine (2-F-Phe), m-fluorophenylalanine (3-F-Phe), p-fluorophenylalanine (4-F-Phe), m-fluorotyrosine (3-F-Tyr), homoserine (Hse), homophenylalanine (Hfe), homotyrosine hydroxylysine (Hyl), isohydroxylysine (aHyl), 5-hydroxytryptophan (5-OH-Trp), 3- or 4-hydroxyproline (3- or 4-Hyp), p-iodophenylalanine-isotyrosine (3-I-Tyr), dihydroindole-2-carboxylic acid (Idc), iso-idoxuridine (Ide), isoleucine (α-Ile), isoperidinic acid (Inp), N-methylisoleucine (MeLys) ), m-methyltyrosine (3-Me-Tyr), N-methylvaline (MeVal), 1-naphthylalanine (1-Nal), 2-naphthylalanine (2-Nal), p-nitrophenylalanine (4-NO2-Phe), 3-nitrotyrosine (3-NO2-Tyr), leucine (Nle), valine (Nva), ornithine (Orn), 1-phosphotyrosine (H2PO3-Tyr), penicillamine, pentafluorophenylalanine (F5-Phe), phenylglycine (Phg), piperidine acid (Pip), propargylglycine (Pra), pyroglutamic acid (PGLU), sarcosine (Sar), tetrahydroisoquinoline-3-carboxylic acid (Tic), thiazolidin-4-carboxylic acid (thioproline, Th).

[0101] As used in this disclosure, the term "peptide" or "polypeptide" refers to a compound formed by the dehydration condensation of two or more amino acid molecules linked together by amide bonds. Generally, the number of amino acids constituting a peptide ranges from 2 (dipeptide) to 20 (eicoseptide).

[0102] As used in this disclosure, the term "residue" refers to the major part of a molecule after a certain group has been removed, such as amino acid residues (e.g., the structure H2NCH2CO-, i.e., glycyl group, which is the part after removing a hydroxyl group from glycine) and peptide residues.

[0103] Sometimes, amino acid residue substituents and peptide residue substituents are simply referred to as amino acid groups and peptide groups. When describing a series of substituents, the expression "substituent is an amino acid" or "substituent is a peptide" is equivalent to "substituent is an amino acid residue" or "substituent is a peptide residue".

[0104] It should be understood that the terms "substitute" or "substituted" as used in this disclosure include the implicit condition that such substitution, with changes in the valence of the substituent atom and the substituent, results in a stable compound (e.g., the compound cannot spontaneously undergo rearrangement, cyclization, elimination, etc.). The term "substituted" as used in this disclosure includes all permissible substituents in organic compounds. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituent organic compounds. There may be one or more substituents. The term "substituted" refers to the substitution of the above-mentioned groups at one or more positions. Substituents include acylamino (including carbamoyl and urea), alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, alkoxycarbonyl, carboxyl, carboxyl, aminocarbonyl, mono- and dialkylaminocarbonyl, cyano, azide, halogen, hydroxyl, nitro, trifluoromethyl, thio, alkylthio, arylthio, alkylthiocarbonyl, thiocarboxylic acid ester, low alkyl, low alkenyl, low alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, low alkoxy, aryloxy, aryloxycarbonyloxy, benzyloxy, benzyl, sulfinyl, alkylsulfinyl, sulfonyl, sulfate, sulfonate, sulfonamide, phosphate, phosphonate, imino, formyl, etc. If permitted, any of the above-mentioned substituents may be further substituted, for example, by alkyl, aryl, or other groups.

[0105] In this disclosure, compound 1 is also referred to as "N-butyryl-4,6-di-O-butyryl-D-glucosamine" or "2-N-4,6-di-O-tributyryl-D-glucosamine". Compound 1 with a larger particle size can be obtained through crystallization, while compound 1 with a smaller particle size can be obtained through pulverization or other means.

[0106] The compounds of this disclosure (I) can be prepared by methods known in the art, such as by substitution of the corresponding hydroxyl groups with the corresponding glucosamine as a starting material. Unless there is obvious conflict, the entire contents of WO2019119117A1 are incorporated herein by reference.

[0107] As used in this disclosure, the term "pharmaceutically acceptable" means that the drug, pharmaceutical product, inert ingredient, etc., described by the term is suitable for contact with the cells or tissues of humans and animals without adverse toxicity, incompatibility, instability, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. It generally refers to compounds, compositions, and formulations approved or permitted by federal or state regulatory agencies or listed in the United States Pharmacopeia or other recognized pharmacopoeia for use in animals, and more particularly for humans.

[0108] The term "pharmaceutically acceptable salt" for a compound of formula (I) refers to a salt of a pharmaceutically acceptable compound. An ideal salt (basic, acidic, or charged functional group) can retain or improve the biological activity and properties of the parent compound as defined in this disclosure, and is not biologically undesirable. A pharmaceutically acceptable salt may be as mentioned by Berge et al. in "Pharmaceutical Salts", J. Pharm. Sci. 66, 1-19 (1977). This includes, but is not limited to:

[0109] (1) Salts formed by adding acids to basic or positively charged functional groups. Inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, aminosulfonic acid, nitric acid, phosphoric acid, carbonates, etc. Organic acids include acetic acid, propionic acid, lactic acid, oxalic acid, glycolic acid, neopentanoic acid, tert-butylacetic acid, β-hydroxybutyric acid, valeric acid, hexanoic acid, cyclopentanepropionic acid, pyruvic acid, malonic acid, succinic acid, malic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, cyclohexylamino Sulfonic acid, benzenesulfonic acid, sulfanilic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 3-phenylpropionic acid, laurylsulfonic acid, lauryl sulfate, oleic acid, palmitic acid, stearic acid, lauric acid, pyruvic acid, pantothenic acid, lactobionic acid, alginic acid, galactobionic acid, galacturonic acid, gluconic acid, glucoheponic acid, glutamic acid, naphthoic acid, hydroxynaphthoic acid, salicylic acid, ascorbic acid, stearic acid, mucoconic acid, etc.

[0110] (2) When the parent compound contains an acidic proton or is replaced by a metal ion, a base can be added to obtain a salt. The metal ions include alkali metal ions (e.g., lithium, sodium, potassium), alkaline earth metal ions (magnesium, calcium, barium), or other metal ions such as aluminum, zinc, and iron. Organic bases include, but are not limited to, N,N'-dibenzylethylenediamine, ethanolamine, diethanolamine, triethanolamine, aminobutanetriol, N-methylglucosamine, piperazine, chloroprocaine, procaine, choline, and lysine.

[0111] Pharmaceutically acceptable salts can be synthesized from parent compounds containing basic or acidic fragments using conventional chemical methods. Typically, such salts are prepared by reacting a compound (free acid or base) with an equistoichiometric amount of base or acid in water, an organic solvent, or a mixture of both. Salts can be prepared in situ during the final separation or purification of the pharmaceutical preparation, or by reacting a purified compound of this disclosure in its free acid or base form separately with the desired corresponding base or acid and then separating the resulting salt. The term "pharmaceutically acceptable salt" also includes zwitterionic compounds containing cationic groups covalently bonded to anionic groups, which are referred to as "internal salts." The compounds of this disclosure include all acids, salts, bases, and other ionic and nonionic forms. For example, if a compound in this disclosure is an acid, its salt form is also included. Similarly, if a compound in this disclosure is a salt, its acid and / or base forms are also included.

[0112] As used in this disclosure, the term "composition" includes pharmaceutical compositions or non-pharmaceutical compositions thereof (e.g., health products, nutritional products or other similar products).

[0113] In this disclosure, "wt%" refers to weight percentage. Except for the coating layer (or coating material), the "wt%" of each component in the compositions of this disclosure is the weight percentage of that component relative to the total weight of the compositions of this disclosure excluding the coating layer (or coating material, if any). In this disclosure, the "wt%" of the coating layer or coating material (such as a coating premix) is the weight gain relative to the total weight of the compositions of this disclosure excluding the coating layer (or coating material).

[0114] As is common knowledge in the art, particle size can be determined using conventional methods for measuring and representing particle size, such as Malvern particle size analysis, sieving, light scattering, optical microscopy, image analysis, sedimentation, and other methods known to those skilled in the art. In this disclosure, particle size can be determined according to Method 3 of Appendix 0982, Determination of Particle Size and Particle Size Distribution, Part IV of the 2020 Chinese Pharmacopoeia. In the following examples, the measurement conditions were as follows: using a Malvern 2000 / 3000 or other equivalent instrument, a Scirocco 2000set / AEROS or other equivalent dispersion unit, a vibration rate of 55%, and a dispersion air pressure of 2.5 bar.

[0115] In this disclosure, "D90" means that 90% by volume of the particle size (or particle diameter) is below the given value, "D50" means that 50% by volume of the particle size (or particle diameter) is below the given value, and "D10" means that 10% by volume of the particle size (or particle diameter) is below the given value.

[0116] In this disclosure, the term "room temperature" refers to the normal room temperature, which is generally 10-30°C.

[0117] As used in this disclosure, the term "AUC" is the area under a curve representing the concentration of a compound in a biological sample of a treated subject as a function of time following administration of the compound to the treated subject. Examples of biological samples include non-limiting biological fluids such as plasma, blood, cerebrospinal fluid (CSF) and saliva, organ homogenates such as brain and liver homogenates, and the like. The AUC can be determined by measuring the concentration of the compound in a biological sample at different time intervals using liquid chromatography-tandem mass spectrometry (LC / MS / MS) and calculating the area under the time period. Methods for calculating AUC from drug concentration-time curves are well-known and recognized in the art. In connection with the disclosure of this disclosure, the AUC of GlcNBu can be determined by detecting the concentration of GlcNBu in plasma, blood, or tissue homogenate after oral administration of the compound described in this disclosure to a treated subject.

[0118] In this disclosure, the parameters used to characterize plasma or blood concentration versus time curves include the area under the curve (AUC) and the time to peak concentration (T). max ) and maximum drug concentration (C max ). Term "C max "T" refers to the maximum concentration of a compound in a patient's biological sample after a given dose of the compound has been administered. max "This refers to the maximum concentration (C0) of the compound in the biological sample of the treated individual after a certain dose of the compound has been administered." max (Time) "T 1 / 2 "It refers to the terminal elimination half-life of the compound in the subject's biological sample after a certain dose of the compound has been administered to the subject."

[0119] When the disclosed compound is used as a prodrug of GlcNBu, the above-mentioned area under the curve (AUC) and peak concentration time (T) are as follows. max Maximum drug concentration (C) max ) and "T" 1 / 2 "All refer to the total area under the curve (AUC) and peak concentration time (Tc) of the compound of formula (I) and GlcNBu after they are converted to GlcNBu in the subject's body." max ), maximum drug concentration (C max ) and "T" 1 / 2 ".

[0120] The term “prevention” means at least reducing the likelihood of acquiring a disease or condition (or susceptibility) or developing a disease or disorder (i.e., preventing the development of clinical symptoms of at least one disease into patients who may be exposed to or susceptible to the disease but have not yet experienced or shown symptoms of the disease).

[0121] In some embodiments, the term "treatment" as used herein refers to the improvement of at least one disease or condition (i.e., cessation or reduction of the development of a disease or at least one clinical symptom thereof) after treatment of any disease or condition. In some embodiments, "treatment" refers to improving a physical parameter of a patient, which may or may not be identifiable to the patient. In some embodiments, "treatment" refers to suppressing a disease or condition physically (e.g., stabilization of identifiable symptoms), physiologically (e.g., stabilization of physical parameters), or both. In some embodiments, "treatment" refers to improving quality of life or reducing symptoms or side effects of bone or joint diseases such as osteoporosis or arthritis in a subject in need. "Therapeutic effective amount" refers to an amount of compound sufficient to treat or prevent a disease when administered to a subject. "Therapeutic effective amount" will vary depending on the subject's disease to be treated or prevented, the disease and its severity, and age, weight, etc. As used herein, the term "therapeutic effective amount" refers to an amount of compound or composition sufficient to prevent, treat, suppress, reduce, improve, or eliminate one or more causes, symptoms, or complications of a bone or joint disease, such as osteoporosis, osteopenia, or arthritis. In some implementations, the desired therapeutic effect is to achieve one or more of the following in the subject: enhanced cartilage formation; enhanced chondrocyte proliferation or growth; reduced joint stiffness; increased mobility or reduced mobility restriction; enhanced glucosamine production; increased bone mineral density (BMD); improved bone microstructure and / or bone connectivity; and reduced fracture risk.

[0122] The term "subject" includes animals, including mammals and humans, especially humans. In this disclosure, "subject" and "patient" are sometimes used interchangeably.

[0123] To better understand this disclosure and to more clearly demonstrate how to implement it, features of embodiments according to this disclosure are now illustrated by way of example.

[0124] Example

[0125] This disclosure will be more readily understood by referring to the following embodiments, which are used to illustrate this disclosure and should not be construed as limiting the scope of this disclosure in any way.

[0126] Unless otherwise defined or the context clearly requires, all technical and scientific terms used in this application have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. It should be understood that any methods and materials similar to or equivalent to those described in this application may be used in the practice or testing of this disclosure. Unless otherwise stated, the materials and instruments used in this application...

[0127] In the following examples and comparative examples, the microcrystalline cellulose used is PH 102.

[0128] In the following examples and comparative examples, the lactose used is 80.

[0129] In the following examples and comparative examples, the mannitol used is mannitol. 200SD.

[0130] Example 1

[0131] Prepare a 500mg / tablet composition containing compound 1 according to the formulation in Table 2. The preparation method is as follows:

[0132] (1) Mix compound 1, filler, disintegrant and lubricant in the internal part evenly, dry granulate, and pass through a 24-mesh sieve to obtain dry granules; the particle size of compound 1 is shown in Table 3.

[0133] (2) Mix the dry granules with the disintegrant, glidant and lubricant in the added part evenly, and compress into tablets;

[0134] (3) Prepare a coating solution with a concentration of about 10% for coating material and then coat the material.

[0135] Example 2

[0136] Prepare compositions containing compound 1 in 100 mg / tablet and 500 mg / tablet strengths according to the formulations in Table 2, using the same preparation method as in Example 1.

[0137] Example 3

[0138] Prepare compositions containing compound 1 in 100 mg / tablet and 500 mg / tablet strengths according to the formulations in Table 2, using the same preparation method as in Example 1.

[0139] Example 4

[0140] Prepare compositions containing compound 1 in 100 mg / tablet and 500 mg / tablet strengths according to the formulations in Table 2, using the same preparation method as in Example 1.

[0141] Example 5

[0142] Prepare compositions containing compound 1 in 100mg / tablet and 500mg / tablet specifications according to the formulation in Table 2. The preparation method is basically the same as in Example 1, except that a surfactant is added in the mixing step (1).

[0143] Example 6

[0144] Compositions containing compound 1 in 100 mg / tablet and 500 mg / tablet strengths were prepared according to the formulations in Table 2, using the same method as in Example 1.

[0145] Comparative Example 1

[0146] 500 mg of compound 1 is filled into hard capsules. The particle size of compound 1 is shown in Table 3.

[0147] Comparative Example 2

[0148] According to the formula in Table 2, mix compound 1, microcrystalline cellulose, lactose, and croscarmellose sodium evenly, then add magnesium stearate and mix evenly. Fill the mixture powder into hard capsules.

[0149] Table 2. Formulations of Examples 1 to 6 and Comparative Examples 1 to 2 (where "%" refers to weight percentage)

[0150] Table 3. Particle size distribution of compound 1 in Examples 1 to 6 and Comparative Examples 1 to 2

[0151] Test Example 1: Process Operability

[0152] During the dry granulation process, it was observed that the materials in Examples 1 and 3-6 had good flowability, and the materials did not adhere to the rollers throughout the granulation process. The material flowability of Examples 2 and Comparative Example 1 was slightly worse than that of Examples 1 and 3-6.

[0153] It can be seen that the D90 particle size of compound 1, ranging from 200μm to 400μm, can meet the requirements of dry granulation for material flowability and compressibility.

[0154] Test Example 2 Dissolution Determination

[0155] The tablets from Examples 1-6 and the capsules from Comparative Examples 1-2 were tested for the dissolution rate of compound 1 according to Method II of Dissolution and Release Determination in Appendix 0931 of the 2020 edition of the Chinese Pharmacopoeia, Part IV. The test conditions were: rotation speed 50 rpm, water bath temperature 37 ± 0.5 °C, dissolution medium 900 mL, and dissolution medium was pH 4.5 acetate buffer solution. The test results are shown in Table 4.

[0156] Table 4. Dissolution rate of compound 1 in Examples 1 to 6 and Comparative Examples 1 to 2

[0157] It can be seen that the tablets of Examples 1-6 all showed good dissolution of compound 1 after 30 minutes. However, the capsules of Comparative Examples 1 and 2 showed insufficient dissolution of compound 1 after 30 minutes.

[0158] Test Example 3: Pharmacokinetic Study

[0159] Samples from Examples 1 and 5 (500mg strength) were selected for pharmacokinetic studies in beagle dogs. Oral administration was used, with two male beagle dogs in each group. Blood samples were collected at regular intervals (5 min, 10 min, 20 min, 30 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, and 6 h) after administration for substance analysis. A control group was established with Comparative Example 1. The results are shown in Table 5 below.

[0160] Table 5. Pharmacokinetic parameters of Examples 1 and 5 and Comparative Example 1

[0161] As can be seen from Table 5, compared with Comparative Example 1, both Example 1 and Example 5 have a longer half-life T. 1 / 2 Furthermore, the exposure levels (AUC) and Cmax of the sample in Example 1 were similar to those in Comparative Example 1, meeting the requirements for clinical drug use. Although the Cmax of Example 5 was slightly lower than that of Comparative Example 1, the exposure level was close to that of Comparative Example 1.

[0162] Test Example 4 Stability Test

[0163] Impurities in the tablets of Examples 1, 2, and 5 were analyzed using high-performance liquid chromatography (HPLC), and the results are shown in Table 6 below. Table 6 shows that compound 1 in the coated tablets prepared using the dry granulation process exhibits good stability, and its content remains essentially unchanged.

[0164] Table 6. Impurity analysis results of Examples 1, 2 and 5

[0165] In addition, the stability of compound 1 in water was tested (HPLC method), and the results are shown in Table 7 below.

[0166] Table 7. Stability of Compound 1 in Water

[0167] It can be seen that when compound 1 is in water, the total impurities gradually increase over time, indicating its instability in water. When using a wet process, the impurity content in the composition increases significantly, posing a risk of degradation for compound 1. Furthermore, compound 1 has a melting point of approximately 87°C-94°C; if higher temperatures are used in the preparation process (e.g., high-temperature drying), compound 1 risks melting.

[0168] Test Example 5 Storage Stability

[0169] The storage stability of the tablets from Example 1 was investigated. They were stored at 40°C and 75% RH for 6 months, and at 25°C and 60% RH for 2 years. Impurities were analyzed using high-performance liquid chromatography (HPLC), and the results are shown in Table 8 below. The results indicate that the tablets from Example 1 exhibit good storage stability.

[0170] Table 8. Storage stability of Example 1

[0171] Based on the above test results, it can be seen that the composition containing glucosamine derivatives disclosed herein has excellent dissolution performance and good stability. It remains stable even under long-term storage conditions, with low growth of related substances and a relatively long half-life, which is beneficial for use as a drug or health product for the prevention or treatment of joint and bone diseases in mammals, such as arthritis or osteoporosis.

[0172] Although this disclosure has been described in detail with reference to embodiments thereof, these embodiments are provided for illustration and not for limitation. Other embodiments that can be obtained based on the principles of this disclosure are within the scope defined by the claims of this disclosure.

Claims

1. A composition containing a glucosamine derivative, comprising: 55 wt% to 70 wt%, preferably 55 wt% to 65 wt%, more preferably 60 wt% to 65 wt% of a compound of formula (I) or a pharmaceutically acceptable salt thereof, based on the total weight of the composition, and a pharmaceutically acceptable excipient; Where R 2 It is hydrogen, acyl, or alkyl; R 1 R 3 R 4 and R 5 Independently hydrogen, substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, alkylaryl, hydrocarbon group containing a carbide ring or heterocycle, or Q 1 C(O)-, amino acid residues (including natural and non-natural amino acid residues), peptide residues, phosphonyl group, sulfonyl group, amino group, condition R 1 R 3 R 4 and R 5 They are not both hydrogen; Q 1 The substituted or unsubstituted groups are selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, cycloalkyl, heterocycloalkyl, alkoxy, aryloxy, and arylalkoxy; optionally, Q 1 The -NH2 and -OH groups in the substance, if present, can further substitute for protecting groups.

2. The composition according to claim 1, wherein, R 2 It is hydrogen; and / or R 1 R 3 R 4 and R 5 Each group is independently selected from alkoxycarbonyl, aryloxycarbonyl, and arylalkoxycarbonyl, or each group is independently H, C1-C12 alkyl acyl, or α-amino acyl derived from natural amino acids. 1 Selected from alkoxy, aryloxy, and arylalkoxy groups; and / or Q 1 Selected from alkoxy, aryloxy, and arylalkoxy groups.

3. The composition according to any one of claims 1 to 2, wherein, R 1 For H, and R 3 R 4 and R 5 Each group is independently selected from H, C1-C6 alkyl acyl groups, and α-amino acyl groups derived from glycine, alanine, valine, leucine, isoleucine, and phenylalanine, provided that R 3 R 4 and R 5 Not both H; or R 1 and R 3 Both are H, and R 4 and R 5 Each can be independently selected from the group consisting of H, C1-C6 alkyl acyl groups, and α-amino acyl groups derived from glycine, alanine, valine, leucine, isoleucine, and phenylalanine, provided that R... 4 and R 5 They are not both H.

4. The composition according to any one of claims 1 to 3, wherein, The compounds are selected from the compounds in the following table or their pharmaceutically acceptable salts:

5. The composition according to any one of claims 1 to 4, wherein, The compound meets one or more of the following characteristics: D90 particle size is above 150μm, or above 200μm, or above 300μm, or above 400μm; D50 particle size is above 30μm; D10 particles have a size greater than 4μm.

6. The composition according to claim 5, wherein, The compound meets one or more of the following characteristics: The D90 particle size is 150μm-500μm; preferably 200μm-400μm, for example, about 300μm; D50 particle size is 30μm-100μm; The D10 particle size is 10μm-50μm, preferably 15μm-20μm.

7. The composition according to any one of claims 1 to 6, wherein, Pharmaceutically acceptable excipients include one or more of fillers, disintegrants, flow aids, lubricants, and surfactants.

8. The composition of claim 7, comprising: based on the total weight of the composition, 5wt%-30wt% filler; 10wt%-30wt% disintegrant; 1wt%-3wt% of glidant; 1wt%-6wt% lubricant; Surfactants of 0.5wt%-2wt%.

9. The composition of claim 7, comprising: based on the total weight of the composition, 5wt%-25wt%, preferably 10wt%-22.5wt% of filler; 15wt%-25% disintegrant; 1.5wt%-2.5wt% of glidant; 2wt%-5wt% lubricant; Surfactants of 0.5wt%-2wt%.

10. The composition according to any one of claims 7 to 9, wherein, The filler is selected from one or more of microcrystalline cellulose, lactose, starch, mannitol, calcium dihydrogen phosphate, sorbitol, xylitol, and magnesium carbonate; The disintegrant is selected from microcrystalline cellulose, sodium carboxymethyl starch, croscarmellose sodium, croscarmellose calcium, croscarmellose polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, croscarmellose alginate, sodium alginate, potassium alginate, gellan gum, pregelatinized starch, corn starch, carboxymethyl cellulose, glycine, and any combination thereof. The flow aid is selected from colloidal silica, talc, magnesium trisilicate, powdered cellulose, starch, and any combination thereof; The lubricant is selected from magnesium stearate, stearic acid, calcium stearate, aluminum stearate, zinc stearate, sodium stearoyl fumarate, hydrogenated castor oil, PEG 4000-8000, talc, glyceryl monostearate, glyceryl dibehenate, glyceryl palmitate stearate, hydrogenated cottonseed oil, castor oil, and any combination thereof; And / or, the surfactant is selected from sodium dodecyl sulfate, poloxamer, stearic acid, povidone, and any combination thereof.

11. The composition according to any one of claims 7 to 10, wherein, The composition further comprises a coating material, such as an immediate-release coating premix, preferably in an amount of 2 wt% to 5 wt% of the total weight of the composition excluding the coating material, for example 3 wt%.

12. The composition according to any one of claims 7 to 11, wherein, The composition comprises 50wt%-70wt% of compound 1, 2wt%-7wt% of microcrystalline cellulose, 5wt%-20wt% of lactose, 10wt%-25wt% of sodium carboxymethyl starch, 1wt%-3wt% of colloidal silica, 2wt%-6wt% of magnesium stearate and 0wt%-2wt% of sodium dodecyl sulfate, and the D90 particle size of compound 1 is greater than 100μm; Alternatively, the composition comprises 60wt%-65wt% of Compound 1, 2wt%-7wt% of microcrystalline cellulose, 5wt%-20wt% of lactose, 10wt%-25wt% of sodium carboxymethyl starch, 1.5wt%-2.5wt% of colloidal silica, 3wt%-5wt% of magnesium stearate and 0wt%-2wt% of sodium dodecyl sulfate, and the D90 particle size of Compound 1 is 100μm-500μm; Alternatively, the composition comprises 55wt%-70wt% of Compound 1, 2wt%-7wt% of microcrystalline cellulose, 3wt%-8wt% of mannitol, 10wt%-25wt% of sodium carboxymethyl starch, 1.5wt%-2.5wt% of colloidal silica, 2wt%-6wt% of magnesium stearate and 0wt%-2wt% of sodium dodecyl sulfate, and the D90 particle size of Compound 1 is in the range of 100μm-500μm.

13. The composition according to any one of claims 1 to 12, wherein, The composition is a solid dosage form, preferably including capsules, pills, tablets, powders, granules, pellets, lozenges, or sugar-coated pills.

14. The composition according to any one of claims 1 to 13, wherein, The composition includes an intraparticle component and an extraparticle component, as well as an optional coating material.

15. The composition according to claim 14, wherein, The in-particle components include 50wt%-70wt% of a compound or a pharmaceutically acceptable salt thereof, 5wt%-30wt% of a filler, 7wt%-12.5wt% of a disintegrant, 1wt%-2.5wt% of a lubricant and 0wt%-2wt% of a surfactant; The extraparticle components include 3wt%-12.5wt% of a disintegrant, 1wt%-3wt% of a flow aid, and 1wt%-3.5wt% of a lubricant.

16. A method for preparing the composition of any one of claims 1 to 15, wherein the method uses a dry granulation process or a powder direct compression process.

17. The method according to claim 16, wherein, The preparation method using dry granulation technology includes the following steps: 1a) The compound of formula (I) or a pharmaceutically acceptable salt thereof, the filler, the disintegrant of the granule component, the lubricant of the granule component and the surfactant (if any) are mixed evenly, and then dry granulated, and sieved to obtain dry granules. 1b) Mix the dry granules, the disintegrant of the extragranule components, the glidant, and the lubricant of the extragranule components evenly, and compress into tablets; 1c) Optionally, the tablets are coated with the coating material; Alternatively, the preparation method using a dry granulation process includes the following steps: 2a) The compound of formula (I) or a pharmaceutically acceptable salt thereof, the filler, the disintegrant of the granule component, the lubricant of the granule component and the surfactant (if any) are mixed evenly, and then dry granulated, and sieved to obtain dry granules; 2b) Mix the dry granules, the disintegrant of the extragranule components, the flow aid, and the lubricant of the extragranule components evenly, and then fill the capsules; The preparation method using powder direct pressing technology includes the following steps: The compound of formula (I) or a pharmaceutically acceptable salt thereof, the filler, the disintegrant, the glidant, and the surfactant (if any) are mixed evenly, and then mixed evenly with the lubricant, and then compressed into tablets or capsules.

18. The method according to claim 17, wherein it is any one of method 1, method 2 or method 3 below; Method 1: 1a) The compound of formula (I) or a pharmaceutically acceptable salt thereof, the filler, the disintegrant of the granule component, the lubricant of the granule component and the surfactant (if any) are mixed evenly, and then dry granulated, and sieved to obtain dry granules. 1b) Mix the dry granules, the disintegrant of the extragranule components, the glidant, and the lubricant of the extragranule components evenly, and compress into tablets; 1c) Optionally, the tablets are coated with the coating material; Method 2: 2a) The compound of formula (I) or a pharmaceutically acceptable salt thereof, the filler, the disintegrant of the granule component, the lubricant of the granule component and the surfactant (if any) are mixed evenly, and then dry granulated, and sieved to obtain dry granules; 2b) Mix the dry granules, the disintegrant of the extragranule components, the flow aid, and the lubricant of the extragranule components evenly, and then fill the capsules; Method 3: The compound of formula (I) or a pharmaceutically acceptable salt thereof, the filler, the disintegrant, the glidant, and the surfactant (if any) are mixed evenly, and then mixed evenly with the lubricant, and then compressed into tablets or capsules.

19. Use of the composition of any one of claims 1 to 15 in the preparation of a medicament for the prevention or treatment of bone or joint diseases in a subject in need, or in the preparation of a health product for the prevention of bone or joint diseases, or in the preparation of an additive for the prevention of bone or joint diseases.

20. The use as described in claim 19, wherein, The bone or joint disease is osteoporosis, osteopenia, and / or arthritis, preferably osteoarthritis, inflammatory arthritis (including rheumatoid arthritis or psoriatic arthritis), traumatic arthritis, degenerative arthritis, or developmental dysplastic arthritis.

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