Compounds, compositions and uses for the prevention or treatment of canine bone or joint diseases

Abstract

This application discloses compounds, compositions, and uses for the prevention or treatment of canine bone or joint diseases. The compounds are those represented by formula (A) and their pharmaceutically acceptable salts and esters, wherein R is an amino acid.

Description

Technical Field

[0001] This invention relates to glucosamine derivatives, pharmaceutical compositions thereof, and their use in the preparation of medicaments for treating, preventing or delaying the onset of bone or joint diseases in canines and maintaining the health of bones and joints in animals. Background Technology

[0002] Degenerative joint disease, also known as osteoarthritis (OA), is a condition characterized by pain and limping associated with pathological changes in the synovial joint tissues, including the loss of articular cartilage.

[0003] In canines, osteoarthritis typically causes joint dysfunction, manifesting as stiffness, decreased mobility, and varying degrees of inflammation and pain. Clinical studies show that the incidence of osteoarthritis in dogs is 42.5% for the hip, 18.5% for the knee, and 12.8% for the elbow, with the incidence increasing with age. Older animals have lower repair capabilities, making age a significant factor in the disease's progression. Obesity and / or excessive exertion can worsen the condition. Commonly kept pet breeds such as Golden Retrievers, Labrador Retrievers, Chow Chows, Pekingese, Pugs, and Teddy Bear Dogs are frequently seen in clinical practice as susceptible to the disease.

[0004] Clinical diagnosis of canine osteoarthritis relies heavily on physical examination. On radiographic imaging, osteoarthritis presents as osteophytes, calcification at ligament attachments, soft tissue mineralization (intra-articular, capsule-, or extra-articular), and soft tissue swelling. To maintain joint function and slow the progression of OA, the main treatments for affected dogs include physical therapy, use of nonsteroidal anti-inflammatory drugs (NSAIDs), joint support, weight and exercise control, intra-articular injections, and surgery.

[0005] While the benefits of glucosamine (GlcN) in bone and joint diseases remain controversial, N-acetylation and other N-acylation of GlcN fundamentally alter its biological properties. In a rat model of destructive arthritis, N-butyrylglucosamine (GlcNBu) significantly preserves subchondral bone structure. Drug applications of GlcNBu have been reported in the literature, see, for example, US Patent Publication No. 6,479,469 (titled "Treatment of Arthritis and Compositions Therefore") and US Patent Publication No. 2006 / 0046976 (titled "Method for Increasing the Bone Mineral Density and Bone Micro-architecture or Connectivity of a Mammalusing N-acylated Glucosamines"), the contents of which are incorporated herein by reference in their entirety.

[0006] Derivatives and / or prodrugs, pharmaceutical compositions of N-butyrylglucosamine (GlcNBu), and the effects of these derivatives in the treatment of osteoporosis, arthritis and other musculoskeletal diseases in humans, have been reported in patent applications CN111971290A and CN109929001A, the contents of which are incorporated herein by reference in their entirety.

[0007] However, glucosamine and GlcNBu have limited therapeutic potential due to their poor pharmacokinetic properties. Glucosamine is usually administered in high doses (e.g., 3 g / day; see Barclay, TS et al., The Annals of Pharmacotherapy, 1998, 32(5): 574-579). Due to its low oral bioavailability (F) (as determined in rats) (F: 0.19-0.21; Aghazadeh-Habashi, A et al.; J. Pharm. Pharm. Sci., 2002, 5: 181-4), canines require an average of 20 mg / lb of glucosamine daily. Even after administration of very high doses to canines, its serum concentration is difficult to detect because glucosamine is rapidly cleared from the circulatory system after oral or intravenous administration. Summary of the Invention

[0008] The purpose of this invention is to improve at least some of the deficiencies in the prior art, enhance bioavailability, stability, and / or reduce the metabolic rate of compounds in canines, thereby increasing the efficacy of glucosamine N-acyl derivatives, such as GlcNBu, in the treatment of canine bone and joint diseases. These and other needs can be met through the glucosamine derivatives and / or prodrugs, pharmaceutical compositions, and the use of these derivatives in the treatment of canine bone and joint diseases, including osteoporosis, arthritis, and other musculoskeletal disorders, disclosed in this invention.

[0009] To address the aforementioned problems, a first aspect of this application provides a compound as shown in formula (A) or a pharmaceutically acceptable salt or ester thereof:

[0010]

[0011] Where R represents an amino acid residue.

[0012] According to a preferred embodiment, the amino acid is selected from natural amino acids in the group consisting of glycine, alanine, valine, histidine, leucine, isoleucine, and phenylalanine.

[0013] In some embodiments, R is a residue selected from the group consisting of L-glycine, L-alanine, L-leucine, and L-isoleucine.

[0014] In some embodiments, the amino acid does not include valine.

[0015] The compound according to formula (A) is an α-terminal isomer; in another embodiment, the compound according to formula (A) is a β-terminal isomer; in yet another embodiment, the compound according to formula (A) is a mixture of α- and β-terminal isomers.

[0016] More preferably, R is derived from L-isoleucine or L-alanine.

[0017] In some embodiments, the C, H, O and N in the compounds of the present invention are each independently atoms of natural abundance or atoms enriched by isotopes.

[0018] In some embodiments, each C atom in the compound of the present invention is independently […]. 12 C 13 C or 14 C, each H atom is independently 1 H, 2 H or 3 H, each O atom is independent 16 O、 17 O or 18 O, and / or each N atom independently for 14N or 15 N.

[0019] Preferably, at least one atom of C, H, O and N in the compound of the present invention is an isotopically enriched atom.

[0020] In embodiments of the present invention, unless otherwise specified, the groups involved in the definition of R above conform to the definition which will be detailed below.

[0021] In some embodiments, the -NH2 and / or -OH groups in the compounds defined above may be further replaced with protecting groups. The protecting group is not particularly limited and may be any protecting group known to those skilled in the art that can be used for amino and hydroxyl groups. In a preferred embodiment, the protecting group may be butoxycarbonyl, preferably tert-butoxycarbonyl (Boc-).

[0022] In some embodiments, the compounds of formula (A) are shown in Table 1, or their pharmaceutically acceptable salts or esters.

[0023] Table 1. GlcNBu derivatives

[0024]

[0025]

[0026] In some embodiments, the compounds of the present invention can be prodrugs of GlcNBu. To avoid being limited by existing theories, these compounds will be converted to GlcNBu in vivo after administration. Therefore, the compounds of the present invention can serve as prodrugs of GlcNBu. In this embodiment, administration of the compounds of the present invention can increase the therapeutic efficacy for canine skeletal and joint diseases such as degenerative osteoarthritis and / or arthritis compared to direct administration of GlcNBu itself. Compared to administration of GlcNBu and / or some prodrugs of GlcNBu, the bioavailability, stability, and / or metabolism of GlcNBu in canines are increased. Specifically, this includes at least one of the following effects: increased bioavailability of GlcNBu; increased area under the curve (AUC) of GlcNBu concentration in blood or plasma; increased maximum drug concentration (C) of GlcNBu. max Increase the peak concentration time of GlcNBu (T) max ); Improves the half-life of GlcNBu (t 1 / 2 It can improve the therapeutic biodistribution of GlcNBu; increase the therapeutic level of GlcNBu in selected tissues; increase the bioabsorption of GlcNBu; reduce the metabolism of GlcNBu; and reduce the side effects of GlcNBu.

[0027] A second aspect of this application provides a pharmaceutical composition. The pharmaceutical composition comprises a compound of the present invention or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable carrier. In some embodiments, a pharmaceutical composition is provided comprising a compound having formula (A) or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable carrier, wherein the compound is not a derivative of N-acetylglucosamine.

[0028] Furthermore, the pharmaceutical composition of the present invention is a controlled-release agent, preferably an enteric-coated controlled-release agent.

[0029] Preferably, the pharmaceutical composition is suitable for oral administration.

[0030] In some embodiments, the pharmaceutical composition is suitable for administration by injection, including intramuscular injection, intraperitoneal injection, intra-articular injection, or intravenous injection.

[0031] In other embodiments, the pharmaceutical composition is suitable for external use.

[0032] Specifically, the pharmaceutical composition may be in the form of capsules, pills, tablets, powders, granules, lozenges, solutions, ointments, creams, or patches.

[0033] Furthermore, the capsule is a hard capsule, a soft capsule, or a flat capsule.

[0034] Furthermore, the pill is a sugar-coated pill.

[0035] Furthermore, the tablet is a lozenge.

[0036] Furthermore, the solution is in the form of an aqueous liquid suspension, a non-aqueous liquid suspension, an oil-in-water liquid emulsion, an oil-in-water liquid emulsion, a syrup, an elixir, or a tincture.

[0037] Furthermore, the ointment is an ointment.

[0038] Furthermore, the patch is a poultice patch.

[0039] A third aspect of this application provides the use of the compounds or pharmaceutical compositions of the present invention in the preparation of medicaments for the treatment and / or prevention of bone or joint diseases in mammals, particularly canines.

[0040] On the one hand, the methods provided by the present invention are used for bone and / or joint diseases including but not limited to osteoporosis, osteoporosis, and / or joint diseases.

[0041] On the other hand, the joint diseases mentioned are osteoarthritis (including hip dysplasia, knee joint disease, osteochondrosis, hypertrophic arthritis), inflammatory arthritis (including rheumatoid arthritis or psoriatic arthritis), degenerative arthritis, traumatic arthritis, or developmental dysplastic arthritis.

[0042] Preferably, the present invention provides a method for preventing or treating degenerative joint diseases in canines, comprising administering an effective amount of the compounds and / or pharmaceutical compositions described herein to a test subject. Degenerative joint diseases are diseases that lead to the progressive loss of articular cartilage and subchondral bone, and symptoms may include joint pain, tenderness, stiffness, locking, and sometimes effusion. Most commonly, degenerative joint diseases are referred to as osteoarthritis, although it may encompass other diseases including degenerative processes that typically cause pain.

[0043] In this invention, degenerative joint disease is understood as a condition or symptom that occurs in test dogs with degenerative joint disease, such as lameness in animals with osteoarthritis in their legs.

[0044] In some embodiments, administration of the compounds of the present invention or pharmaceutical compositions thereof may increase the bioavailability of GlcNBu in canines, the AUC of GlcNBu in blood or plasma, and the C60 of GlcNBu compared to administration of GlcNBu itself. max 、GlcNBu's T max Improve the t of GlcNBu 1 / 2 Therapeutic biodistribution of GlcNBu and / or in vivo bioabsorption of GlcNBu.

[0045] In other embodiments, in canines, administration of the compounds of the present invention or pharmaceutical compositions thereof increases the bioavailability of GlcNBu, the AUC of GlcNBu in blood or plasma, and the C60 of GlcNBu compared to some disclosed prodrugs. max 、GlcNBu's T max Improve the t of GlcNBu 1 / 2 Therapeutic biodistribution of GlcNBu and / or in vivo bioabsorption of GlcNBu.

[0046] In some embodiments, the effective concentration of GlcNBu in selected tissues of diseased dogs is increased after administration of the compound of the present invention or a pharmaceutical composition thereof, compared with administration of GlcNBu itself.

[0047] In other embodiments, the effective concentration of GlcNBu in selected tissues of diseased dogs is increased after administration of the compounds of the present invention or pharmaceutical compositions thereof, compared with the administration of some disclosed prodrugs of GlcNBu.

[0048] In some embodiments, administration of the compounds of the present invention or pharmaceutical compositions thereof may reduce the in vivo metabolism of GlcNBu compared to administration of GlcNBu itself.

[0049] In other embodiments, administration of the compounds of the present invention or pharmaceutical compositions thereof may reduce the in vivo metabolism of GlcNBu compared to administration of some disclosed prodrugs of GlcNBu.

[0050] In some embodiments, administration of the compounds of the present invention or pharmaceutical compositions thereof reduces the side effects of GlcNBu in vivo compared to administration of GlcNBu itself.

[0051] In other embodiments, administration of the compounds of the present invention or pharmaceutical compositions thereof may reduce the side effects of GlcNBu in vivo compared to administration of some disclosed prodrugs of GlcNBu.

[0052] In some embodiments, administration of the compounds of the present invention or pharmaceutical compositions thereof may enhance the production of glucosamine in test dogs compared with administration of GlcNBu itself.

[0053] In other embodiments, administration of the compounds of the present invention or pharmaceutical compositions thereof may enhance the production of glycosaminoglycans in test dogs compared to administration of some disclosed prodrugs of GlcNBu.

[0054] A fourth aspect of this application provides a treatment kit comprising one or more compounds or pharmaceutical compositions described in this invention. The treatment kit may further include instructions for use, for example, specific instructions on how to use the treatment kit to treat or prevent bone or joint conditions such as osteoporosis, osteopenia, or arthritis.

[0055] This invention can improve at least some of the defects in the prior art, improve the bioavailability and stability of compounds in canines and / or reduce the metabolism of compounds, reduce side effects, improve the bioavailability of active pharmaceutical ingredients, and better achieve the effect of treating canine bone or joint diseases. Attached Figure Description

[0056] To better understand the present invention and more clearly illustrate how to implement it, further description will now be given with reference to the accompanying drawings by way of embodiments, which illustrate various aspects and features of embodiments according to the present invention, wherein:

[0057] Figure 1 The curves (drug-time curves) showing the average plasma concentration of GlcNBu relative to time after oral administration of compound 2 and GlcNBu at equimolar doses; experimental animals: beagle dogs.

[0058] Figure 2The curves (drug-time curves) showing the average plasma concentration of GlcNBu relative to time after oral administration of compound 3 and GlcNBu at equimolar doses; experimental animals: beagle dogs.

[0059] Figure 3 Comparison of mean plasma concentrations of GLcNBu relative to time after oral administration of equimolar doses of compounds 1, 2, 3 and 4 of the present invention; experimental animals, beagle dogs. Detailed Implementation

[0060] definition

[0061] For convenience, the meanings of certain terms and phrases used in this invention are provided below. Unless otherwise specified, all technical and scientific terms used in this invention have the same meanings as commonly understood by one of ordinary skill in the art.

[0062] When used in conjunction with the term "comprising" in the claims and / or description, the quantifier "a" can mean "one or a kind," but it also means "one or more," "at least one or a kind," and "one or more than one." Similarly, the phrase "another or another kind" can mean at least a second / second type or more / more kinds. Furthermore, the singular form of "a" can mean both singular and plural.

[0063] 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, steps or processes.

[0064] The terms “about” or “approximately” are used to indicate values, including those determined to be due to errors in instruments and methods.

[0065] The term "derivative" as used in this invention should be understood as another compound that is structurally similar but differs in some minor structural features.

[0066] 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.

[0067] As used in this invention, 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.

[0068] As used in this invention, 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.

[0069] A residue refers to the main part of a molecule after a certain group is removed, such as an amino acid residue (e.g., the structure H2NCH2CO-, i.e., glycyl group, which is the part after removing a hydroxyl group from glycine).

[0070] Sometimes, amino acid residue substituents are simply referred to as amino acid groups. When describing a series of substituents, the statement "the substituent is an amino acid" is equivalent to "the substituent is an amino acid residue".

[0071] It should be understood that the terms "substitute" or "substituted" as used in this invention 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 invention includes all permissible substituents in organic compounds.

[0072] Isotope enrichment is a process in which the relative abundance of a given element's isotopes is increased (i.e., enhanced), while the corresponding other isotope is reduced or depleted. An isotopically enriched compound refers to a compound in which one or more specific elements are enriched in isotopes that are not naturally abundant. As used in this invention, the term "isotopically enriched element" refers to the enrichment (i.e., the enrichment or enhancement) of one or more specific isotopes of a particular atom in a compound. Typically, in an isotopically enriched compound or derivative, a specific isotope at a specific position in the compound is enriched or enhanced. However, it should be understood that a compound may have two or more isotopes enriched or enhanced, including different isotopes of the same type of atom and individual isotopes of different types of atom. Furthermore, isotopically enriched compounds can be a mixed form of isotope enrichment, i.e., containing multiple specific isotopes or elements, or both.

[0073] Typically, deuterium (D or 2 H (its stable isotope with a mass approximately twice that of hydrogen), nitrogen-15 ( 15 N), carbon-13 ( 13 C), Oxygen-18 ( 18 O) and oxygen-17 ( 17 The natural abundances of O are 0.016%, 0.37%, 1.11%, 0.204%, and 0.037%, respectively. The "isotope-enriched" compounds or derivatives used in this invention have isotope levels higher than these natural abundances. The level of isotope enrichment depends on the natural abundance of the specific isotope itself. In some embodiments, the isotope enrichment level of the compound or the element in the compound can be from about 1 to about 100 molar percentages (%), for example, about 2%, about 5%, about 17%, about 30%, about 51%, about 83%, about 90%, about 95%, about 96%, about 97%, about 98%, and greater than about 98%, about 99%, or 100%. In one embodiment, the isotope enrichment level of the isotope-enriched compound of this invention is about 5% or higher, or about 10% or more. In another embodiment, the isotope enrichment level of the isotope-enriched compound of this invention is about 20% or higher, or about 50% or more. In another embodiment, the isotope enrichment level of the isotope-enriched compound of the present invention is about 75% or higher, or about 90% or higher. In another embodiment, the isotope enrichment level of the isotope-enriched compound of the present invention is about 95% or higher, or 100%. In another embodiment, the isotope enrichment level of the isotope-enriched compound of the present invention is about 98% to 100%.

[0074] It is worth noting that the level of isotopic enrichment of a particular compound or a particular element of a compound will depend on several properties of the compound, including chemistry, pharmacokinetics and therapeutic effects, with the aim of improving the compound’s therapeutic efficacy, therapeutic biodistribution, bioavailability, metabolism, stability and / or pharmacokinetics.

[0075] The term "naturally abundant element" as used in this invention refers to the element with the most abundant atomic mass in nature. For example, the naturally abundant element of hydrogen is [missing information]. 1 H, the element with the highest natural abundance of nitrogen. 14 N; the element with the highest natural abundance of oxygen is 16 O, the element with the highest natural abundance of carbon. 12 C. "Non-isotopic enriched" compounds are compounds in which all atoms or elements are naturally abundant isotopes, meaning that the atomic mass of all atoms or elements is the most abundant in nature.

[0076] Unless otherwise specified, the compounds and compositions described in this invention are non-isotope-enriched compounds or compounds enriched with one or more isotopes.

[0077] A “pharmaceutically acceptable salt” of a compound refers to a salt of a pharmaceutically acceptable compound. Ideally, the salt of a compound (basic, acidic, or charged functional group) should retain or improve the biological activity and properties of the parent compound as defined in this invention, and should not be biologically undesirable. Pharmaceutically acceptable salts can be those mentioned by Berge et al. in “Pharmaceutical Salts”, J. Pharm. Sci. 66, 1-19 (1977). These include, but are not limited to:

[0078] (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, cyclohexylaminosulfonic acid, benzene Sulfonic 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, primordic 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.

[0079] (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 basic 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.

[0080] 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 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 the invention in 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 the present invention include all acids, salts, bases, and other ionic and nonionic forms. For example, if the compound in the present invention is an acid, the salt form of that compound is also included. Similarly, if the compound in the present invention is a salt, the acidic and / or base forms of that compound are also included. In some embodiments, the present invention relates to pharmaceutically acceptable salts of compounds. As understood by those skilled in the art, various salts (e.g., triethylamine salts, tetrazolium salts, sodium salts, potassium salts, etc.) are possible, including suitable salts known in the art. The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable, non-toxic acid or base (including inorganic acids and bases, as well as organic acids and bases). For example, for compounds containing basic nitrogen, their salts can be prepared from pharmaceutically acceptable, non-toxic acids (including inorganic and organic acids). Pharmaceutically acceptable acids suitable for use in the present invention include, but are not limited to, acetic acid, benzenesulfonic acid (benzenesulfonates), benzoic acid, camphorsulfonic acid, citric acid, vinylsulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucilage, nitric acid, pyric acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, etc. When the compound contains an acidic side chain, the pharmaceutically acceptable bases suitable for use in this invention include, but are not limited to, metal salts made of aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or organic salts made of lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucosamine) and procaine.

[0081] The term "pharmaceutically acceptable ester" of a compound refers to an esterified form of a pharmaceutically acceptable compound, which is substantially non-toxic to organisms and hydrolyzes in organisms to form the compound of the present invention or its salts.

[0082] In some embodiments, the pharmaceutically acceptable "ester" of the compounds of the present invention includes, but is not limited to, esterifications obtained by reacting at least one hydroxyl group of the compounds of the present invention with general formula R'COOH (carboxylic acid) or general formula R'SO3H (sulfonic acid).

[0083] As used in this invention, the term "AUC" refers to 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 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 the 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 accepted in the art. In connection with the disclosure of this invention, 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 herein to a treated subject.

[0084] As used in this invention, "bioavailability" refers to the rate and amount of drug that reaches the systemic circulation of a patient after administration of the drug or prodrug, and can be determined by evaluating, for example, the plasma or blood concentration versus time distribution of the compound. Parameters used to characterize plasma or blood concentration versus time curves include the area under the curve (AUC), 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 (The time) "t 1 / 2 "Bioavailability is the terminal elimination half-life of a compound in a biological sample from a test dog after a certain dose of the compound has been administered. Bioavailability is usually expressed as F(%), which is the percentage of the compound's AUC after a specific route of administration (e.g., oral) relative to the compound's AUC after intravenous (IV) administration."

[0085] When the compound of the present invention 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 "These all refer to the area under the curve (AUC) and peak concentration time (T) of the compound of this invention after it is converted to GlcNBu in the test dogs." max Maximum drug concentration (C) max ) and "t 1 / 2 ".

[0086] As used in this invention, "bioequivalence" refers to the equivalence of the rate and extent of absorption of a drug (e.g., a compound) after administration of the same dose to a patient. As used herein, two plasma or blood concentration distributions are bioequivalent if the 90% confidence intervals of the average response rates of the two distributions are within the limits of 0.8 and 1.25. The average response includes at least one characteristic parameter of the distribution, such as C0. max T max And AUC.

[0087] As used in this invention, the term "effective amount" refers to the quantity or dosage of a compound that provides the desired effect in a patient undergoing diagnosis or treatment after administration of a single or multiple doses. The effective amount can be readily determined by the attending physician or diagnostician using known techniques and by observing results obtained under similar conditions. In determining the effective amount or dosage of a compound, the attending physician or diagnostician considers many factors, including but not limited to: the patient's weight or size, age and general health, the specific disease involved, the extent or severity of the disease, the individual patient's response, the specific route of administration of the compound, the bioavailability characteristics of the administered formulation, the chosen dosing regimen, the use of concurrent drug therapy, and other relevant circumstances.

[0088] As used in this invention, the term "pharmaceuticalally acceptable" means that the drug, pharmaceutical product, inert ingredient, etc., described by this term is suitable for contact with the cells or tissues of humans and animals without adverse toxicity, incompatibility, instability, irritation, allergic reactions, etc., and is commensurate with a reasonable benefit / risk ratio. It generally refers to compounds, compositions, and formulations approved or permitted by federal or state government regulatory agencies, or listed in the United States Pharmacopeia or other recognized pharmacopoeias, for use in animals, and more particularly for humans.

[0089] "Pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient, carrier, or support for administering a compound. The terms "pharmaceutically acceptable carrier" and "pharmaceutical acceptable support" are used interchangeably herein.

[0090] "Pharmaceutical composition" means comprising the compounds described herein and at least one pharmaceutically acceptable carrier, diluent, adjuvant, excipient, or such excipient as preservative, filler, disintegrant, wetting agent, emulsifier, suspending agent, sweetener, flavoring agent, aromatizer, antimicrobial agent, antifungal agent, lubricant, dispersant, etc., depending on the route of administration and dosage form.

[0091] "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 a disease but have not yet experienced or shown symptoms of the disease).

[0092] In some embodiments, the term "treatment" as used herein refers to the improvement of at least one disease or symptom (i.e., cessation or reduction of the development of the 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 symptom 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 test dogs in need. "Therapeutic effective amount" refers to an amount of compound sufficient to treat or prevent a disease when administered to a test dog. "Therapeutic effective amount" will vary depending on the compound in the test dog with the 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 test dogs: 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.

[0093] "Therapeutic efficacy" refers to the ability of a compound or composition to provide a desired therapeutic effect. As used herein, the term "increased therapeutic efficacy" means increasing the therapeutic effect provided by a specific active therapeutic agent. In some embodiments, "increased therapeutic efficacy" means improving the pharmacokinetics of the therapeutic agent, such as obtaining one or more target pharmacokinetic parameters, thereby improving or enhancing the ability of the therapeutic agent to achieve the desired therapeutic effect. In some embodiments, "increased therapeutic efficacy" means increasing one or more of the following: the bioavailability of GlcNBu; the AUC of GlcNBu in blood or plasma; the C60 of GlcNBu. max ;GlcNBu's T max The half-life of GlcNBu (t 1 / 2 The biodistribution of GlcNBu; the level of GlcNBu in selected tissues; and / or the bioabsorption of GlcNBu; in one subject, compared to administration of GlcNBu itself. In some embodiments, “increasing therapeutic efficacy” means reducing one or more of the following: the metabolism of GlcNBu; and the side effects of GlcNBu; in one subject, compared to administration of GlcNBu itself. In some embodiments, “increasing therapeutic efficacy” means reducing the dose and / or frequency of administration of a compound or composition sufficient to provide the desired therapeutic effect in test dogs.

[0094] The term "test dog" includes canines, particularly dogs.

[0095] As used in this invention, the terms "prodrug" and equivalent expressions refer to a pharmaceutical form that can be directly or indirectly converted into an active compound in vitro or in vivo (see, for example, R.B. Silverman, 1992, "The Organic Chemistry of Drug Design and Drug Action", Academic Press, Chap. 8; Bundgaard, Hans; Editor. Neth. (1985), "Design of Prodrugs", 360pp. Elsevier, Amsterdam; Stella, V.; Borchardt, R.; Hageman, M.; Oliyai, R.; Maag, H.; Tilley, J. (Eds.) (2007), "Prodrugs: Challenges and Rewards", XVIII, 1470p. Springer). Prodrugs can be used to alter biodistribution (e.g., allowing the drug to enter the reaction site of a protease that it would not normally enter) or the pharmacokinetics of a particular drug. A wide variety of groups can be used to modify compounds to form prodrugs, such as esters, ethers, phosphates, etc. When a prodrug is administered to a treated individual, the group is cleaved or non-cleaved, reduced, oxidized, hydrolyzed, or otherwise released to release the active compound. As used herein, "prodrug" refers to a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate, as well as any crystalline form of the aforementioned drugs. Prodrugs are often (but not necessarily) pharmacologically inactive before conversion to their active form.

[0096] Preparation method

[0097] The compounds of this invention can be prepared using methods known in the art, such as by substituting the corresponding hydroxyl group into the starting material of the corresponding glucosamine. Taking compound A of formula A as defined above as an example, it can generally be prepared from N-butyryl-D-glucosamine by esterification at the hydroxyl group at position 1. For substituents containing amino and / or hydroxyl groups, the amino and / or hydroxyl groups can be protected before the reaction, for example using the most common Boc protection, to avoid unwanted side reactions. After the reaction, the protection is removed, and a pharmaceutically acceptable salt, such as a hydrochloride, can be further prepared.

[0098] These preparation methods are all conventional methods in the field, and it is believed that those skilled in the art can choose the appropriate synthetic route according to actual needs. Therefore, they will not be described in detail here.

[0099] Pharmaceutical Composition

[0100] In one embodiment, the pharmaceutical composition of the present invention comprises any compound of formula (A) as defined above, or a pharmaceutically acceptable salt, ester, or solvate thereof, and a pharmaceutically acceptable carrier. In one embodiment, the pharmaceutical composition of the present invention comprises a specific compound mentioned in the present invention (the compounds in Table 1), or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier thereof. In another embodiment, the pharmaceutical composition of the present invention comprises any compound of formula (A) as defined above and a specific compound in Table 1, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier thereof, provided that the compound is not an N-acetyl-glucosamine derivative.

[0101] Pharmaceutical compositions can be prepared by methods known in the art (e.g., see Remington: The Science and Practice of Pharmacy, 20th Edition, 2000). For example, compounds and / or compositions may be combined with one or more solid or liquid drug carrier substances and / or additives (or excipients) and other active compounds with therapeutic or preventative effects (if desired) to form a suitable route of administration or dosage form, which is then administered as a drug to canines. Pharmaceutical preparation may involve the addition of many additives known in the art, such as fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, dispersants, preservatives, sweeteners, colorants, flavoring agents, aromatizers, thickeners, diluents, buffers, solvents, solubilizers, reagents for achieving reservoir effects, salts for altering osmotic pressure, coating agents, and / or antioxidants, etc.

[0102] The term "pharmaceutically acceptable carrier" as used in this invention is intended to include any carrier, diluent, adjuvant, excipient, or mediator described herein. Non-limiting examples of suspending agents include ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar, and tragali gum, or mixtures thereof. Antimicrobial action can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, etc. Isotonic agents, such as sugars and sodium chloride, may also be added. Prolonged absorption of injectable drugs can be achieved by using delayed absorption agents, such as aluminum monostearate and gelatin. Non-limiting examples of suitable carriers, diluents, solvents, or mediators include water, ethanol, polyols, suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters (ethyl oleate). Non-limiting examples of excipients include lactose, lactose monohydrate, sodium citrate, calcium carbonate, and dicalcium phosphate. Non-limiting examples of disintegrants include starch, alginate, and certain complex silicates. Non-limiting examples of lubricants include magnesium stearate, sodium lauryl sulfate, talc, and high molecular weight polyethylene glycol.

[0103] Pharmaceutically acceptable carriers may include any or all physiologically acceptable solvents, dispersion media, coatings, antibacterial agents, antifungal agents, isotonic agents, absorption delay agents, etc. In one embodiment, the carrier is suitable for oral administration, and may also be suitable for intravenous, intraperitoneal, intramuscular, sublingual, or parenteral administration. In other embodiments, the carrier is suitable for local administration or administration by inhalation. Pharmaceutically acceptable carriers may include sterile aqueous solutions or dispersions and sterile powders that can be used for the provisional preparation of sterile injectable solutions or dispersions. Such media and reagents for pharmaceutically active substances are disclosed in the art. Except for some conventional media or reagents incompatible with the active compound, the pharmaceutical compositions of the present invention are likely to achieve the desired results.

[0104] The pharmaceutical compositions of this invention can be administered orally, for example, in the form of pills (e.g., sugar-coated pills), tablets (e.g., lacquer tablets, sugar-coated tablets, lozenges), powders, lozenges, granules, hard and soft (gelatin) capsules, capsules, aqueous solutions, alcoholic (or oily) solutions, syrups, emulsions, suspensions, oil-in-water emulsions, water-in-oil emulsions, elixirs, or syrups. They can also be administered rectally, for example, in the form of suppositories. Parenteral administration is also possible, for example, subcutaneous, intramuscular, or intravenous administration via injection or infusion. Other suitable routes of administration are intradermal or transdermal, for example, in the form of ointments (e.g., ointments, creams), creams, patches (e.g., poultices), tinctures, sprays, or transdermal therapeutic systems. They can also be administered by inhalation in the form of nasal sprays or aerosol mixtures. Alternatively, they can be administered via microcapsules, implants, or wafers.

[0105] In some embodiments, the pharmaceutical composition may or may not form an enteric coating. In some embodiments, the pharmaceutical composition is formulated into a formulation that controls drug release, such as by delaying release or prolonging the release time.

[0106] In a further embodiment, the compound and its composition can be formulated into multiple dosage forms, i.e., in the form of a multi-particulate dosage form (e.g., hard gelatin capsules or conventional tablets prepared using a rotary tablet press), comprising one or more beads or mini-tablets for oral administration to a patient. Conventional tablets disperse rapidly upon entering the stomach. One or more coated beads or mini-tablets can be compressed together with appropriate excipients into the corresponding tablet (e.g., binders, diluents / fillers, and disintegrants for conventional tablets, etc.).

[0107] Tablets, pills, beads, or small tablets of compounds or compositions thereof may be coated or otherwise compounded to control drug release (including delayed release or prolonged release time) or to protect it from degradation by acidic mediators in the stomach. For example, a tablet or pill may contain an internal dose component and an external dose component, the latter serving as a coating for the former. The two components may be separated by a polymer layer to control the release process of the internal dose.

[0108] In some embodiments, the layer may comprise at least one enteric polymer. In other embodiments, the layer may comprise a composition of at least one enteric polymer and at least one water-insoluble polymer. In yet another embodiment, the layer may comprise a composition of at least one enteric polymer and at least one water-soluble polymer. In still another embodiment, the layer may comprise a composition of at least one enteric polymer and a pore-forming agent.

[0109] In some embodiments, the layer may comprise at least one water-insoluble polymer. In other embodiments, the layer may comprise a composition of at least one water-insoluble polymer and at least one water-soluble polymer. In still other embodiments, the layer may comprise a composition of at least one water-insoluble polymer and a pore-forming agent.

[0110] Representative examples of water-soluble polymers include polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), and polyethylene glycol.

[0111] Representative examples of enteric polymers include cellulose esters and their derivatives (cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate), polyvinyl acetate phthalate, pH-sensitive methacrylate-methyl methacrylate copolymers, and shellac. These polymers can be used as dry powders or aqueous dispersions. Some commercially available materials include methacrylate copolymers manufactured by Rohm Pharma under the trademark Eudragit (LI 00, SI 00, L30D); Cellacefate (cellulose acetate phthalate) manufactured by Eastman Chemical Co.; Aquateric (cellulose acetate aqueous dispersion) manufactured by FMC Corp.; and Aqoat (hydroxypropyl methylcellulose acetate succinate aqueous dispersion) manufactured by ShinEtsu KK.

[0112] Representative examples of non-water-soluble polymers include ethyl cellulose, polyvinyl acetate (e.g., Kollicoat SR#30D produced by BASF), cellulose acetate, cellulose acetate butyrate, neutral copolymers based on ethyl acrylate and methyl methacrylate, and copolymers of acrylic acid and methacrylate with quaternary ammonium groups (e.g., Eudragit NE, RS and RS30D, RL or RL30D, etc.).

[0113] Any of the above-described polymers can be plasticized with one or more pharmaceutically acceptable plasticizers. Representative examples of plasticizers include compounds or mixtures thereof such as triglycerides, tributyl citrate, triethyl citrate, acetyl tri-n-butyl citrate, diethyl phthalate, castor oil, dibutyl sebate, and acetylated monoglycerides. When using plasticizers, they can constitute about 3 to 30% of the polymer by weight, typically about 10 to 25% by weight. The type and amount of plasticizer depend on the properties of the polymer or multiple polymers and coating systems (e.g., based on aqueous or solvent-based, solution or dispersion, and total solids properties).

[0114] Pharmaceutical compositions must generally be sterile and stable under manufacturing and storage conditions. Compositions can be formulated as solutions, microemulsions, liposomes, or other ordered structures suitable for high concentrations of the drug. The solvent or dispersion medium of the carrier may contain, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. Appropriate flowability can be achieved by using coatings (e.g., lecithin) and adding surfactants to the dispersion to maintain the desired particle size. In many cases, isotonic agents, such as sugars, polyols such as mannitol, sorbitol, or sodium chloride, may be added to the composition. The purpose of prolonging the absorption of injectable compositions can be experimentally explored by adding agents that delay absorption (e.g., monostearate and gelatin). Furthermore, compounds can be formulated into timed-release formulations, for example, by adding polymers that enable slow release. The compound can be prepared by adding carriers that prevent rapid release, such as controlled-release formulations, including implants and microencapsulated delivery systems. Biodegradable and biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoester, polylactic acid, and polylactic acid-polyglycolic acid copolymer (PLG).

[0115] Many methods for preparing such formulations are generally well known to those skilled in the art. Sterile injectable solutions can be prepared by adding an appropriate amount of an active compound, such as any compound of formula (A), to a solvent, and sterilizing by filtration, as needed, in combination with one or more of the ingredients listed above. Dispersions are typically prepared by adding an active compound to a dispersion medium containing a sterile carrier and the ingredients listed above. In preparing sterile powders from sterile injectable solutions, a common method is to add a powder containing the active ingredient, obtained through vacuum drying and freeze-drying, to a sterile filtered solution containing the desired ingredients. Compound formulations can also be prepared by adding one or more compounds that enhance their solubility.

[0116] For ease of administration and uniform dosage, it is generally advantageous to formulate parenteral compositions in unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable for a single dose in canines, each unit containing a predetermined amount of active substance calculated to produce the desired therapeutic effect, along with a suitable drug carrier. The specifications of the unit dosage form of the present invention are variable and are governed by and directly dependent on (a) the unique characteristics of the therapeutic compound and the unique therapeutic effect to be achieved, and (b) the inherent limitations in formulating such a therapeutic compound. Dosage will be discussed further below.

[0117] In some embodiments, the pharmaceutical composition includes an effective amount of the compound and / or a combination thereof, as well as a pharmaceutically acceptable carrier.

[0118] In one embodiment, a pharmaceutical composition for treating or preventing bone or joint disorders is provided, comprising the compounds described herein or their pharmaceutically acceptable salts or esters, and including a pharmaceutically acceptable carrier.

[0119] In one embodiment, a pharmaceutical composition for treating or preventing osteoporosis is provided, comprising a compound described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In one embodiment, a pharmaceutical composition for treating or preventing arthritis is provided, comprising a compound described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier thereof.

[0120] In some embodiments, when the compounds and treatment methods of the present invention are administered to the treated group, there is an acceptable difference between the treatment or prevention methods of the present invention and the placebo group or historical control group.

[0121] It should be understood that the use of one or more active compounds and / or combinations, and the choice of their dosage, depends on the individual's basic condition (which should generally be optimized for the individual). Dosing and administration regimens should be within the capabilities of a person skilled in the art, and appropriate dosages depend on many factors, including the knowledge and competence level of a general technical physician, veterinarian, or researcher (see Wells et al. eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000)). For example, dosing and administration can depend on the condition itself and its severity, as well as the sex, age, weight, and individual responsiveness of the treated animal, the effective duration and half-life of the compound, whether the treatment is acute, chronic, or prophylactic, and / or whether other active compounds are administered in addition to the therapeutic active substance.

[0122] Therefore, the dosage of a compound or composition depends on a variety of factors, including but not limited to: the activity, biological and pharmacokinetic properties, and / or side effects of the compound used; the age, weight, general health condition, and diet of the test dog; the timing and route of administration, excretion rate, and any applicable drug combinations; the desired effect of the compound on the treated individual; the properties of the compound administered (e.g., bioavailability, stability, efficacy, toxicity, etc.); and the established rational dosage recognized in the art. When administering one or more of the compounds or compositions described herein to canines, a veterinarian may initially prescribe a relatively low dose, subsequently increasing the dose until an appropriate response is obtained.

[0123] There are no particular limitations on the dosage of each compound involved in the present invention used in the composition. Example dosages include milligrams or micrograms of the compound per kilogram of treated subject or sample weight (e.g., about 50 micrograms per kilogram to about 3000 milligrams per kilogram, about 1 milligram per kilogram to about 100 milligrams per kilogram, about 1 milligram per kilogram to about 50 milligrams per kilogram, about 1 milligram per kilogram to about 10 milligrams per kilogram, or about 3 milligrams per kilogram to about 5 milligrams per kilogram). Other example dosages include about 5-500 mg, about 25-300 mg, about 25-200 mg, about 50-150 mg, or about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, 500 mg, about 1000 mg, about 2000 mg, and about 3000 mg, for example, lower or higher doses, such as daily or twice daily.

[0124] In some embodiments, the oral dose for adult dogs is typically 0.005 mg to 10 g / day. Formulations in tablet or other forms can conveniently contain an amount (such a dose or multiples thereof is an effective dose) of the compound (e.g., general formula A). For example, containing 5 mg to 500 mg, typically about 10 mg to 200 mg. Dosage units of the compound (e.g., oral dosage units) may include, for example, 1-30 mg, 1-40 mg, 1-100 mg, 1-300 mg, 1-500 mg, 2-500 mg, 3-100 mg, 5-20 mg, 5-100 mg (e.g., 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg). g, 18mg, 19mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, approximately 1000mg, approximately 2000mg, and approximately 3000mg).

[0125] In some embodiments, the oral dosage of the compound typically ranges from about 0.001 mg to about 3000 mg per kilogram of body weight. In some embodiments, the oral dosage is 0.01 mg to 100 mg per kilogram of body weight, 0.1 mg to 50 mg per kilogram of body weight, 0.5 mg to 20 mg per kilogram of body weight, or 1 mg to 10 mg per kilogram of body weight. In some embodiments, the oral dosage is 5 mg of the compound per kilogram of body weight.

[0126] The compounds and compositions of this invention, when applied to treated dogs using known methods and dosages, achieve desired therapeutic effects within an effective timeframe. Dosing regimens can be adjusted as needed to achieve optimal therapeutic efficacy. For example, the dose can be divided into multiple daily administrations, or the dose can be reduced proportionally for emergency treatment situations. In some embodiments, treated dogs, under the action of effective doses of the compound or composition, can prevent or treat skeletal or joint diseases such as osteoporosis and arthritis. Furthermore, the compound or composition can be administered via any suitable route or method, such as, but not limited to, oral, parenteral, intravenous, intraperitoneal, intramuscular, sublingual, local or intranasal administration, inhalation, transdermal, or transdermal methods commonly used in the art.

[0127] The compounds and compositions involved in this invention can be administered once, twice, three times, or four times daily in any of the above-described reasonable manner. Furthermore, in some embodiments, the administration or treatment of any compound described in this invention (depending on the compound structure) can last for several weeks. For example, routine treatment can last for at least 2 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 28 weeks, 32 weeks, 36 weeks, 40 weeks, 44 weeks, 48 ​​weeks, 52 weeks, 56 weeks, 60 weeks, 64 weeks, 68 weeks, 72 weeks, 76 weeks, 80 weeks, 84 weeks, 88 weeks, 92 weeks, 96 weeks, 100 weeks, or 104 weeks, etc. In other embodiments, the administration or treatment of any compound described in this invention (depending on the compound structure) can last for several months. For example, routine treatment can last for at least 2 months, 4 months, 6 months, 8 months, 10 months, 12 months, 15 months, 18 months, 20 months, or 24 months, etc. In another embodiment, the application or treatment of any of the compounds described in this invention (depending on the compound structure) can continue indefinitely.

[0128] Treatment

[0129] In some embodiments, methods are provided for treating or preventing bone or joint diseases in test dogs in need, including administering an effective amount of the compound GlcNBu prodrug described herein or a pharmaceutical composition thereof to the test dog, for example, to prevent or treat degenerative bone and / or joint diseases in the test dog.

[0130] The methods provided in this invention can be used to treat or prevent a wide variety of bone or joint diseases, including but not limited to osteoporosis, osteopenia, and / or arthritis. Many types of arthritis are known and can be treated or prevented using the methods provided herein, including but not limited to osteoarthritis, inflammatory arthritis (e.g., rheumatoid arthritis, psoriatic arthritis, etc.), traumatic arthritis, degenerative arthritis, and developmental dysplastic arthritis.

[0131] In one embodiment, a method for enhancing glycosaminoglycan production in test dogs is provided.

[0132] In some embodiments, a method is provided to increase the therapeutic efficacy of GlcNBu in test dogs in need, comprising administering to the test dogs an effective amount of the compound of the present invention or a pharmaceutical composition thereof as a GlcNBu prodrug, such that the therapeutic effect is increased compared to direct administration of GlcNBu.

[0133] In some embodiments, by administering the compounds provided by the present invention, GlcNBu prodrugs, or pharmaceutical compositions, one or more of the following effects are increased: bioavailability of GlcNBu; AUC of GlcNBu in blood or plasma; C60 of GlcNBu. max;GlcNBu's T max ;GlcNBu's t 1 / 2 Therapeutic biodistribution of GlcNBu; therapeutic levels of GlcNBu in selected tissues; and / or bioabsorption of GlcNBu in test dogs, particularly improving the bioavailability of GlcNBu. In some embodiments, administration of the compounds, GlcNBu prodrugs, or pharmaceutical compositions provided herein achieves one or more of the following effects: reduced metabolism compared to direct administration of GlcNBu; reduced side effects in test dogs compared to direct administration of GlcNBu.

[0134] In some embodiments, a method is provided for obtaining targeted pharmacokinetic parameters of GlcNBu in vivo, comprising administering an effective amount of the GlcNBu prodrug or a pharmaceutical composition thereof described herein to a test dog, such that the target obtains the pharmacokinetic parameters of GlcNBu in the test dog. Non-limiting examples of targeted pharmacokinetic parameters include targeted bioavailability, AUC in blood or plasma, C20, etc. max T max Biological distribution, level in selected tissues, half-life (t) 1 / 2 Pharmacokinetic parameters can be calculated using methods known in the art, including bioabsorption and metabolic rates.

[0135] In some embodiments of the methods provided herein, the canines are Beagles, Golden Retrievers, Labrador Retrievers, Chow Chows, Pekingese, Pugs, Teddy dogs, etc., especially Beagles.

[0136] Example

[0137] The invention will be more readily understood by referring to the following embodiments, which are used to illustrate the invention and should not be construed as limiting the scope of the invention in any way.

[0138] Unless otherwise defined or the context clearly specifies otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. It should be understood that any methods and materials similar to or equivalent to those described herein may be used in the practice or testing of this invention. Preparation example:

[0139] Preparation of GlcNBu

[0140] D-glucosamine hydrochloride (100 g, 464 mmol, 1 eq) was dispersed in 1 L of methanol. Triethylamine (94 g, 928 mmol, 2 eq) was added and stirred for 0.5 hours, followed by butyric anhydride (73.4 g, 464 mmol, 1 eq). The mixture was stirred at room temperature for 4–5 hours, and then triethylamine (94 g, 928 mmol, 2 eq) and butyric anhydride (73.4 g, 464 mmol, 1 eq) were added. The reaction mixture was stirred at 35 °C for 15 hours, cooled to room temperature, and then filtered. The filter cake was washed twice with ethanol, then twice with ethyl acetate, and dried to give butyrylglucosamine (53 g, yield 45.8%). 1 H NMR(D2O,500MHz)δppm 0.90-0.94(m,3H),1.59-1.67(m,2H),2.26-2.30(m,2H),3.45-3.55(m,2 H), 3.67-3.92 (m, 4H), 4.70 (d, J = 8.5Hz, 0.6H), 5.20 (d, J = 3.5Hz, 0.4H).

[0141] Preparation of compound a: 4,6-di-O-butyryl-N-butyrylglucosamine (Comparative Example 1)

[0142]

[0143] Step A: Butyrylglucosamine (10.0 g, 40 mmol, 1 eq) was dispersed in 200 mL of N,N-dimethylformamide (DMF). Benzaldehyde dimethyl acetal (60.8 g, 400 mmol, 10 eq) and toluenesulfonic acid monohydrate (0.76 g, 4 mmol, 0.1 eq) were added with stirring. The reaction mixture was stirred at 50 °C for 16 hours. The reaction mixture was cooled to room temperature, poured into 800 mL of water, and stirred for 1 hour. The mixture was filtered, and the filter cake was washed with 100 mL of water, then washed with 100 mL of petroleum ether. After drying, 4,6-O-benzylidene-N-butyrylglucosamine (8.0 g, yield 59.0%) was obtained.

[0144] Step B: 4,6-O-benzylidene-N-butyrylglucosamine (3.37 g, 10 mmol, 1 eq) and benzyl bromide (3.76 g, 22 mmol, 2.2 q) were dispersed in 50 mL of DMF and cooled to -10 °C under nitrogen protection. NaH (1.08 g, 27 mmol, 2.7 eq) was added in portions with stirring, while maintaining the reaction temperature below 0 °C. The mixture was then slowly heated to room temperature and stirred for 2 hours. The reaction solution was poured into 300 mL of water, and the mixture was stirred for 1 hour. After filtration, the filter cake was washed with 50 mL of water, then with 50 mL of petroleum ether, and dried to obtain 1,3-di-O-benzyl-4,6-O-benzylidene-N-butyrylglucosamine (4.5 g, yield 87.1%).

[0145] Step C: 1,3-Di-O-benzyl-4,6-O-benzylidene-N-butyrylglucosamine (4.5 g, 8.7 mmol, 1 eq) was dispersed in 90 mL of dichloromethane (DCM), and 1.5 mL of water and 18 mL of trifluoroacetic acid were added with stirring. The mixture was stirred at room temperature for 10 min. After adding 50 mL of water and stirring, the organic phase was separated. The organic phase was washed with 50 mL of water, followed by 50 mL of saturated sodium bicarbonate solution. The solvent was evaporated, and the residue was hot-powdered with petroleum ether, filtered, and dried to obtain 1,3-Di-O-benzyl-N-butyrylglucosamine (3.2 g, yield 85.7%).

[0146] Step D: 1,3-Di-O-benzyl-N-butyrylglucosamine (2.5 g, 5.8 mmol, 1 eq) was dispersed in 25 mL of pyridine. DMAP (0.04 g, 0.29 mmol, 0.05 eq) and butyric anhydride (2.3 g, 14.5 mmol, 2.5 eq) were added with stirring. After stirring at room temperature for 16 hours, the reaction mixture was poured into 250 mL of water, and the mixture was stirred for 1 hour. The resulting filter cake was obtained by suction filtration, washed with 50 mL of water, then washed with 50 mL of petroleum ether, and dried to obtain 1,3-Di-O-benzyl-4,6-Di-O-butyryl-N-butyrylglucosamine (2.9 g, yield 87.8%).

[0147] Step E: 1,3-Di-O-benzyl-4,6-Di-O-butyryl-N- (2.9 g, 5.1 mmol, 1 eq) was dispersed in 15 mL of methanol (MeOH), 1.45 g of 10% palladium on carbon (Pd / C) was added, followed by 15 mL of acetic acid. After hydrogen purging, the mixture was stirred in a hydrogen atmosphere for 48 hours. The reaction mixture was filtered, the filtrate was evaporated to dryness, and the residue was purified by column chromatography (MeOH / DCM = 1 / 100–1 / 30) to give 4,6-Di-O-butyryl-N-butyrylglucosamine (Comparative Example 1) (1.3 g, yield 65.6%). 1H NMR(CD3OD,500MHz)δppm 0.78-1.03(m,9H),1.52-1.66(m,6H),2.18-2.31(m,6H),3.30(s,0.3H),3.6 2(s,0.7H),3.78-4.11(m,4.3H),4.63(s,0.3H),4.86(t,1H),5.07(s,0.8H). 13 CNMR(CD3OD,125MHz)δppm 12.67,17.97,18.98,35.46,35.58,37.51,37.53,37.92,54.38,54.46,57.51,62.31,69.00,71.1 3,71.49,71.83,91.17,95.69,172.87,172.94,173.55,173.63,173.86,175.13,175.21,175.62. MS(ESI+)m / z:389.8.

[0148] Preparation of compound b: 6-O-(3-cyclopentylpropionyl)-N-butyrylglucosamine (Comparative Example 2)

[0149]

[0150] Step A: 3-Cyclopentylpropionic acid (695.25 mg, 4.89 mmol, 1.05 eq) was dissolved in 22 mL of DMF, followed by the addition of 1,3-di-O-benzyl-N-butyrylglucosamine (2 g, 4.66 mmol, 1 eq), EDCI (1.79 g, 9.31 mmol, 2 eq), HOBt (943.81 mg, 6.98 mmol, 1.5 eq), and DIPEA (1.50 g, 11.64 mmol, 2.5 eq). The reaction mixture was stirred at 25 °C for 24 hours, then diluted with ethyl acetate, and the organic phase was washed three times with water. The organic phase was dried over anhydrous sodium sulfate and then evaporated to dryness. The residue was subjected to silica gel column chromatography (DCM:MeOH, 50:1) to give 1,3-di-O-benzyl-6-(3-cyclopentylpropionyl)-N-butyrylglucosamine (2 g, yield 77.57%).

[0151] Step B: 1,3-Di-O-benzyl-6-(3-cyclopentylpropionyl)-N-butamidoglucose (2 g, 3.61 mmol, 1 eq) was dispersed in a mixed solvent of methanol (10 mL) and acetic acid (10 mL), and 10% palladium on carbon (1 g) was added. The reaction mixture was heated to 50 °C under a hydrogen atmosphere and stirred at this temperature for 24 hours, then filtered. After the filtrate was evaporated to dryness, the residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to give compound b (850 mg, yield 63.01%). 1 H NMR(CD3OD,500Hz)δppm 1.00(m,3H),1.16(m,2H),1.59-1.69(m,8H),1.83(m,3H),2.26(m,2H),2.40(m,2H),3.37-3.50(m,1.4H),3.63-3.73 (m,1H),3.88-4.03(m,1.7H),4.22-4.26(m,1H),4.41-4.45(m,1H),4.65(d,J=7.5Hz,0.2H),5.11(d,J=3.5Hz,0.8H). 13 C NMR(CD3OD,125Hz)δppm 14.86,21.23,27.06,33.27,34.39,35.36,39.96,41.90,56.70,56.79,6 5.76,71.74,73.45,73.57,76.33,76.84,77.05,93.61,176.62,177.52. MS(ESI+)m / z:374.1.

[0152] Preparation of compound c: 6-O-decanoyl-N-butyrylglucosamine (Comparative Example 3)

[0153]

[0154] Decanoic acid was used as the starting material, and the relevant synthesis steps are the same as those for the synthesis of compound b. 1 H NMR(CD3OD,500MHz)δppm 0.84-0.93(m,6H),1.26(s,12H),1.58-1.63((m,4H),2.18-2.31(m,4H),3.27-3.31(m,0.5H),3.35-3.44(m,0.6H),3.5 5-3.69(m,1H),3.81-3.94(m,1.7H),4.15-4.19(m,1H),4.32-4.39(m,1H),4.55-4.57(d,J=8.0Hz,0.2H),5.05(s,1H). 13C NMR(CD3OD,125MHz)δppm 13.97,14.44,20.31,23.68,30.17,30.53,38.88,39.25,55.63,55.71,58.58,64.76,70 .69,72.21,72.43,72.51,75.27,92.57,97.08,175.39,175.49,176.48,176.56,177.10. MS(ESI+)m / z:404.1.

[0155] Preparation of Compound 1: 6-O-(L-leucyl)-N-butyrylglucosamine hydrochloride

[0156]

[0157] Step A: 1,3-Di-O-benzyl-N-butyrylglucosamine (15 g, 34.92 mmol, 1 eq) and N-Boc-L-leucine monohydrate (8.88 g, 35.62 mmol, 1.02 eq) were dissolved in 135 mL of DMF, followed by the addition of 1-hydroxybenzotriazole (HOBt, 7.08 g, 52.39 mmol, 1.5 eq), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 13.39 g, 69.85 mmol, 2 eq), and triethylamine (10.6 g, 104.77 mmol, 3 eq). After stirring at room temperature for 15 hours, the reaction solution was added to 500 mL of water, resulting in the appearance of a white solid. The solid was filtered and purified by silica gel column chromatography (MeOH / DCM, 0%-2%) to give 1,3-di-O-benzyl6-O-(N-Boc-L-leucyl)-N-butyrylglucosamine (14.5 g, yield 64.59%). 1 H NMR(500MHz,CD3OD)δppm7.52-7.17(m,10H),5.54(d,J=3.6Hz,1H),4.88-4.78 (m,2H),4.72(d,J=11.2Hz,1H),4.68-4.43(m,2H),4.41-4.21(m,2H),4.21-4.0 9(m,1H),4.05-3.88(m,1H),3.81-3.71(m,1H),3.60(d,J=9.4Hz,1H),2.23-2.0 6(m,2H),1.85-1.72(m,1H),1.72-1.55(m,4H),1.46(s,9H),1.08-0.86(m,9H).

[0158] Step B: 1,3-Di-O-benzyl6-O-(N-Boc-L-leucyl)-N-butyrylglucosamine (14.5 g, 22.56 mmol, 1 eq) was dispersed in 30 mL of acetic acid and 150 mL of tetrahydrofuran. Pd / C (14.5 g, 5% , 6.81 mmol, 0.3 eq) was added, and the mixture was reacted at 40 °C for 15 h under hydrogen atmosphere. The insoluble matter was removed by filtration, and the filtrate was concentrated and dried to obtain 6-O-(N-Boc-L-leucyl)-N-butyrylglucosamine (10.35 g, yield 99.2%). 1 H NMR (500MHz, CD3OD) δppm 7.84(d,J=8.3Hz,1H),7.03(d,J=8.3Hz,1H),5.12(d,J=3.2Hz,1H),4.69-4 .39(m,1H),4.38-4.11(m,2H),4.08-3.98(m,1H),3.94-3.84(m,1H),3.75( t,J=9.7Hz,1H),3.66(t,J=8.9Hz,0H),3.57-3.45(m,0H),3.44-3.38(m,1H ), 2.27 (t, J = 7.4Hz, 2H), 1.84-1.54 (m, 5H), 1.49 (s, 9H), 1.05-0.91 (m, 9H).

[0159] Step C: 6-O-(N-Boc-L-leucyl)-N-butyrylglucosamine (10 g, 21.62 mmol, 1 eq) was dissolved in 60 mL of DCM, and HCl / dioxane solution (27 mL, 4 M, 5 eq) was added. The mixture was stirred at room temperature for 0.5 hours. After the reaction solution was concentrated, DCM (30 mL) and water (25 mL) were added, the mixture was stirred and allowed to stand, the aqueous phase was separated, and the aqueous phase was freeze-dried to give compound 1 (8.1 g, yield 92.57%) as a pale yellow solid. 1 ¹H NMR (500MHz, D₂O) δppm 5.09(d,J=3.2Hz,0.54H),4.65(d,J=8.3Hz,0.35H),4.51-4.36(m,1.66H),4 .18-4.07(m,1H),4.06-3.91(m,1.61H),3.85-3.75(m,0.52H),3.74-3.56(m ,1.14H),3.51-3.37(m,1.11H),2.41-2.33(m,0.09H),2.29-2.10(m,1.80H) ,1.88-1.75(m,1H),1.75-1.61(m,2H),1.59-1.46(m,2H),0.96–0.71(m,9H). 13CNMR(126MHz,D2O)δ177.81,177.57,170.48,95.01,90.95,73.53,73.07,70.33,70.08,69.79,69.16,64.73 ,64.65,56.40,53.86,51.43,38.84,38.80,37.94,37.52,24.03,21.30,21.26,21.15,21.12,18.95,12.61. MS(ESI+)m / z:363.2.MS(ESI-)m / z:361.1.

[0160] Preparation of Compound 2: 6-O-(L-Isoleucyl)-N-Butyrylglucosamine hydrochloride

[0161]

[0162] Using N-Boc-L-isoleucine as the starting material, the relevant synthesis steps are the same as those for the synthesis of 6-O-(L-leucyl)-N-butyrylglucosamine hydrochloride. 1 H NMR(500MHz,D2O)δppm0.76-0.98(m,9H),1.23-1.33(m,1H),1.35-1.46(m,1H),1.48-1.59(m,2H),2.00-2.06 (m,1H),2.14-2.22(m,1.5H),2.33-2.39(m,0.3H),3.35-3.49(m,1H),3.55-3.72(m,1H),3.77-3.83(m,0.4H), 3.90-4.02(m,0.6H),4.05-4.11(m,1H),4.11-4.25(m,0.5H),4.27-4.44(m,0.6H),4.44-4.47(m,1H),4.47-4. 51 (m, 0.3H), 4.62-4.69 (m, 0.5H), 5.09 (d, J = 3.5Hz, 0.5H), 6.22 (d, J = 3.5Hz, 0.02H), 6.35 (d, J = 5.0Hz, 0.1H). 13C NMR(125MHz,CD3OD)δppm 11.90,12.01,13.72,13.82,13.89,20.48,26.15,26.68,37.38,37.81,38.41,38.63,38.81,54.84,56.17,57. 31,58.30,66.25,68.10,70.42,72.53,78.67,92.39,96.74,103.34,169.70,169.82,177.20,177.50,178.06. MS(ESI+)m / z:363.2.

[0163] Preparation of Compound 3: 6-O-(L-alanyl)-N-butyrylglucosamine hydrochloride

[0164]

[0165] N-Boc-L-alanine was used as the starting material, and the relevant synthesis steps are the same as those for the synthesis of compound 1. 1 H NMR(500MHz,D2O)δppm 0.81-0.92(m,3H),1.51-1.63(m,5H),2.22(q,J=7.5Hz,2H),3.42-3.77(m,3H),3.82-3.91(m,0.5H),3.9 6-4.10(m,0.6H),4.15-4.29(m,1H),4.38-4.57(m,2H),4.70(d,J=8.5Hz,0.6H),5.14(d,J=3.0Hz,0.5H). 13 C NMR(125MHz,D2O)δppm 12.59,15.12,18.95,37.52,37.93,48.77,53.84,56.37,64.80,69.14,69.69,70.00,70.36,73.10,73.51,90.95,95.03,170.48,177.59. MS(ESI+)m / z:321.1.

[0166] Preparation of Compound 4: 6-O-(L-glycyl)-N-butyrylglucosamine hydrochloride

[0167]

[0168] N-Boc-L-glycine was used as the starting material, and the relevant synthesis steps are the same as those for the synthesis of compound 1. 1H NMR(500MHz,D2O)δppm 0.74-0.96(m,3H),1.46-1.65(m,2H),2.11-2.30(m,2H),3.38-3.55(m,1.3H),3.58-3.77(m,1.5 H), 3.79-4.07 (m, 3.3H), 4.34-4.58 (m, 1.8H), 4.68 (d, J = 9.0Hz, 0.5H), 5.13 (d, J = 2.5Hz, 0.5H). 13 C NMR(125MHz,D2O)δppm 12.56,18.94,37.50,37.91,39.98,53.81,56.34,64.59,64.73,69.07,69.63 ,69.93,70.31,73.06,73.46,90.94,95.01,167.89,167.94,177.58,177.81. MS(ESI+)m / z:307.0.

[0169] Test example: Pharmacokinetic study

[0170] General methods for pharmacokinetic studies

[0171] Reagent Preparation: For intravenous bolus administration, physiological saline is used as the solvent. Based on the weighing correction factor, an appropriate amount of physiological saline is added to the original compound vial to prepare a high-concentration stock solution for formulation preparation. The required volume of the stock solution is then transferred to a suitable container, and physiological saline is added to bring the volume to a final volume. The solution is vortexed until completely dissolved, yielding a homogeneous and clear solution. The prepared intravenous formulation is then filtered through a 0.22 μm microporous membrane for sterilization and stored at room temperature until use. Intravenous injection formulations are prepared on the day of administration and subjected to formulation analysis. For gavage administration, physiological saline is used as the solvent. The required volume of the stock solution is transferred to a suitable container, and physiological saline is added to bring the volume to a final volume. The solution is vortexed / stirred until visually homogeneous before administration.

[0172] Animal husbandry and sampling: Thirty-four Beagles (Beijing Mars Biotechnology Co., Ltd.) were housed in an animal room with relative humidity controlled at 40%-70%, temperature controlled at 18-26℃, and air exchanged 10-20 times per hour. The experimental animals were weighed on the day of drug administration and administered the drug according to their weight. Administration methods included oral gavage (PO) and intravenous injection (IV). For oral gavage, the gavage tube was flushed with approximately 6 ml (three times its volume) of solvent after administration. All tubes were of uniform size and length, and the tubes used for each animal were identical, with consistent flushing solvent volume. For intravenous administration, the drug was slowly injected (within 3 minutes) through the cephalic vein or saphenous vein. The blood vessel used for drug administration was not used for blood sampling. The experimental animals were accurately weighed after administration, and their general condition and appearance were observed.

[0173] The test compound was dissolved in a solvent, and its concentration was determined by the desired dose and volume of the compound administered to a specific animal. In the experiment, four beagle dogs were randomly selected from each group and divided into two subgroups. Three beagle dogs were randomly selected to receive the test compound orally, and one was administered it by injection. Different compounds were administered at the same equivalent volume. Measured volumes of the administered solution were administered to the animals (orally or intravenously). Following administration of the test compound, blood samples were collected at specific time points (e.g., 0, 5, 10, 15, 30 minutes, 1, 1.5, 2, 3, 4, and 6 hours). Blood samples were converted to plasma samples using standard techniques. LC-MS / MS analysis was performed to obtain the concentrations of the test compound and GlcNBu in the plasma.

[0174] Pharmacokinetic studies of compounds 1-4 and ac

[0175] Animal grouping: Four Beagle dogs were randomly selected for each treatment group and divided into two groups: three dogs in the gavage group and one dog in the injection group. Compounds 1-4 and ac were formulated into injection and oral formulations respectively according to the above method. The dosage forms were administered at 0.04 mmol / kg and 0.24 mmol / kg, respectively. Specifically: Compound 1 was administered orally at a dose of 87.2 mg / kg to the gavage group and simultaneously injected at a dose of 14.5 mg / kg to the injection group; Compound 2 was administered orally at a dose of 87.2 mg / kg to the gavage group and simultaneously injected at a dose of 14.5 mg / kg to the injection group; Compound 3 was administered orally at a dose of 77.1 mg / kg to the gavage group and simultaneously injected at a dose of 12.9 mg / kg to the gavage group; Compound 4 was administered orally at a dose of 73.7 mg / kg to the gavage group and simultaneously injected at a dose of 12.9 mg / kg to the injection group. Compound a was administered at an injection dose of 0.3 mg / kg to the injection group; compound a was administered orally at a gavage dose of 93.4 mg / kg, and simultaneously injected at a dose of 15.6 mg / kg to the injection group; compound b was administered orally at a gavage dose of 90 mg / kg, and simultaneously injected at a dose of 15 mg / kg to the injection group; compound c was administered orally at a gavage dose of 97.1 mg / kg, and simultaneously injected at a dose of 5 mg / kg (the injection dose with the highest solubility for this compound was used due to its poor solubility). Six beagle dogs were randomly selected, with three receiving GlcNBu via gavage (60 mg / kg, 0.24 mmol / kg) and the other three receiving an injection (10 mg / kg, 0.04 mmol / kg) as a positive control group. Blood samples were collected intravenously at predetermined time points before and after administration, and the plasma GlcNBu concentration was determined using LC / MS-MS.

[0176] Figures 1 to 3 The results of pharmacokinetic studies after the application of different compounds are shown.

[0177] Figure 1 The figure shows the plasma GlcNBu-time concentrations after oral administration of compound 2 and GlcNBu. In this figure, the curves marked with -■- and -◆- represent the plasma GlcNBu concentrations after oral administration of GlcNBu (60 mg / kg) and oral administration of compound 2 (87.2 mg / kg), respectively. The results indicate that compound 2 significantly improved plasma drug exposure, with the Cg of plasma GlcNBu concentration being significantly reduced. max Both AUC and AUC showed some improvement.

[0178] Figure 2The figure shows the plasma GlcNBu concentrations over time after oral administration of compound 3 and GlcNBu. The curves marked with -◆- and -■- represent the plasma GlcNBu concentrations after oral administration of GlcNBu (60 mg / kg) and compound 3 (77.1 mg / kg), respectively. The results indicate that compound 3 improved plasma drug exposure relative to GlcNBu, with the Cg of plasma GlcNBu concentration being... max Both AUC and AUC showed some improvement.

[0179] Figure 3 The curves of plasma GlcNBu concentration versus time were shown in different oral administration examples of compounds 1-4 of the present invention.

[0180] Table 2 provides the results of all pharmacokinetic parameters for compounds 2, 3, and the positive control GlcNBu administered orally.

[0181] Table 2. PK parameters of GlcNBu in blood after administration of compounds 2, 3 and the positive control GlcNBu.

[0182]

[0183]

[0184] AUC (0-8) The area under the drug concentration curve in the (0-8) segment is the area enclosed by the blood drug concentration curve in the (0-∞) segment of the time axis from the initial stage to 8 hours.

[0185] AUC (0-∞) The area under the (0-∞) segment of the drug-time curve is the area enclosed by the blood drug concentration curve over the (0-∞) segment of the time axis.

[0186] t 1 / 2 Half-life: The larger the half-life value, the slower the drug elimination or distribution process.

[0187] T max Time to peak concentration (TBC) is the time required to reach the peak concentration of a drug after administration.

[0188] C max Peak drug concentration, which is the highest blood drug concentration that occurs after drug administration.

[0189] Table 2 shows that, in the PK parameters of compounds 2 and 3, the AUC is improved by 40%-50% compared to GlcNBu, and C max and t 1 / 2 It offers an improvement of over 20% compared to GlcNBu.

[0190] Table 3 shows the results of bioavailability (F%) of compounds 1-4 and compound ac after equimolar oral / intravenous administration.

[0191] Table 3. Application of compounds 1-4 and compound ac * Subsequently, bioavailability parameters

[0192] Compound 1 Compound 2 Compound 3 Compound 4 compound a Compound b Compound C F％ 7.88 14.4 14.8 6.4 3.99 0.42 3.29

[0193] *Compound ac is equivalent to comparative examples 1-3

[0194] As shown in Table 3, the bioavailability parameters of compounds 2 and 3 when administered to dogs were significantly higher than those of other compounds and comparative examples 1, 2, and 3. This means that when compound 2 or compound 3 was administered to the affected dogs, the speed and amount of drug reaching the systemic circulation of the treated individuals were better compared to the comparative examples.

[0195] Although the invention has been described in detail with reference to embodiments thereof, these embodiments are provided for illustration and not limitation. Other embodiments that can be obtained according to the principles of the invention fall within the scope defined by the claims of the invention.

[0196] All cited references and bibliographic information are incorporated into this paper in their entirety through citation.

Claims

1. A compound as shown below, or a pharmaceutically acceptable salt thereof:

2. The compound according to claim 1, wherein C, H, O and N in the compound are each independently a naturally abundant element or an isotopically enriched element.

3. The compound according to claim 2, wherein, Each C atom in the compound is independently... 12 C 13 C or 14 C, each H atom is independently 1 H, 2 H or 3 H, each O atom is independent 16 O、 17 O or 18 O, and / or each N atom independently for 14 N or 15 N.

4. A pharmaceutical composition comprising the compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

5. The pharmaceutical composition according to claim 4, wherein, The pharmaceutical composition is in the form of capsules, pills, tablets, powders, granules, lozenges, solutions, ointments, creams, or patches.

6. The pharmaceutical composition according to claim 5, wherein, The pills are sugar-coated pills.

7. The pharmaceutical composition according to claim 5, wherein, The tablets are lozenges.

8. The pharmaceutical composition according to claim 5, wherein, The solution is in the form of an aqueous liquid suspension, a non-aqueous liquid suspension, an oil-in-water liquid emulsion, an oil-in-water liquid emulsion, a syrup, an elixir, or a tincture.

9. The pharmaceutical composition according to claim 5, wherein, The ointment is an ointment.

10. The pharmaceutical composition according to claim 5, wherein, The patch is a poultice patch.

11. The pharmaceutical composition according to claim 5, wherein, The capsule may be a hard capsule, a soft capsule, or a flat capsule.

12. The pharmaceutical composition according to claim 5, wherein, The pharmaceutical composition is a controlled-release agent.

13. The pharmaceutical composition according to claim 12, wherein, The controlled-release agent is an enteric-coated controlled-release agent.

14. The pharmaceutical composition according to claim 4, wherein, The pharmaceutical composition is suitable for oral administration.

15. The pharmaceutical composition according to claim 4, wherein, The pharmaceutical composition is suitable for injection administration.

16. The pharmaceutical composition according to claim 15, wherein, The pharmaceutical composition is suitable for intramuscular, intraperitoneal, intra-articular, or intravenous injection.

17. The pharmaceutical composition according to claim 4, wherein, The pharmaceutical composition is suitable for external use.

18. The use of the compound according to any one of claims 1-3 or the pharmaceutical composition according to any one of claims 4 to 17 in the preparation of a medicament for the treatment and / or prevention of bone and / or joint diseases in canines.

19. The application according to claim 18, wherein, The bone and / or joint disease is selected from at least one of the groups consisting of osteoporosis, osteoporosis, and arthritis.

20. The application according to claim 19, wherein, The arthritis referred to is osteoarthritis, degenerative arthritis, inflammatory arthritis, traumatic arthritis, or developmental dysplastic arthritis.

21. The application according to claim 20, wherein, The inflammatory arthritis mentioned is rheumatoid arthritis or psoriatic arthritis.

22. The application according to any one of claims 18 to 21, wherein, The canine mentioned is the dog.

23. A treatment kit comprising the compound of any one of claims 1 to 3 or the pharmaceutical composition of any one of claims 4 to 17 and instructions for use.

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