Compound for preventing or treating canine bone or joint diseases, composition, and use

Abstract

The present application discloses a compound for preventing or treating canine bone or joint diseases, a composition, and a use. The compound is a compound represented by formula (A) or a pharmaceutically acceptable salt and ester thereof, wherein R is amino acid.

Description

Compounds, compositions and uses for preventing or treating canine bone or joint diseases Technical Field

[0001] The present invention relates to glucosamine derivatives, pharmaceutical compositions thereof, and applications in preparing medicines for treating, preventing or delaying the onset of canine bone or joint diseases and maintaining animal bone and joint health. Background Art

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

[0003] For canines, osteoarthritis often 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 joint, 18.5% for the knee joint, and 12.8% for the elbow joint, with the incidence increasing with age. Elderly animals have lower repair capacity, making age a significant factor in the disease. Obesity and / or excessive exertion can aggravate the condition. Golden Retrievers, Labradors, Chow Chows, Pekingese, Pugs, and Teddy dogs, among other dog breeds commonly kept in households, are clinically susceptible to the disease.

[0004] Clinical diagnosis of canine osteoarthritis relies heavily on physical examination. Radiographically, osteoarthritis manifests as osteophytes, calcification of ligamentous insertions, soft tissue mineralization (intra-articular, capsular, or extra-articular), and soft tissue swelling. To maintain joint function and slow the progression of OA, primary treatment options for affected dogs include physical therapy, nonsteroidal anti-inflammatory drugs, joint bracing, weight control and exercise, intra-articular injections, and surgery.

[0005] Although the benefits of glucosamine (GlcN) in bone and joint diseases remain controversial, N-acetylation and other N-acylations of GlcN fundamentally change its biological properties. In a rat model of destructive arthritis, N-butyrylglucosamine (GlcNBu) significantly preserved subchondral bone structure. The pharmaceutical applications of GlcNBu have been reported in the literature, see, for example, U.S. Patent Publication No. US 6,479,469 (titled "Treatment of Arthritis and Compositions Therefore") and U.S. Patent Publication No. US 2006 / 0046976 (titled "Method for Increasing the Bone Mineral Density and Bone Micro-architecture or Connectivity of a Mammal using 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 (N-butyrylglucosamine, GlcNBu), and the effects of these derivatives in treating osteoporosis, arthritis and other bone and joint 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, due to poor pharmacokinetic properties, glucosamine and GlcNBu have limited therapeutic potential. Glucosamine is typically administered in large 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 measured 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 per day. Even after very large doses of glucosamine are administered to canines, its serum concentration is difficult to detect because glucosamine is rapidly cleared from the circulation after oral or intravenous administration.

[0008] Summary of the Invention

[0009] The present invention is directed to improving at least some of the deficiencies of the prior art by enhancing the bioavailability, stability, and / or reducing the metabolic rate of the compounds in canines to increase the efficacy of glucosamine N-acyl derivatives, such as GlcNBu, in treating canine bone and joint disorders. These and other needs are met by the disclosed glucosamine derivatives and / or prodrugs, pharmaceutical compositions, and the use of these derivatives in treating canine bone and joint disorders, including osteoporosis, arthritis, and other skeletal and joint disorders.

[0010] In order to solve the above problems, the first aspect of the present application provides a compound represented by formula (A) or a pharmaceutically acceptable salt or ester thereof:

[0011] Wherein, R is an amino acid residue.

[0012] According to a preferred embodiment, the amino acid is selected from the 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 acids do not include valine.

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

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

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

[0018] In some embodiments, each C atom in the compounds 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 independently 16 O. 17 O or 18 O, and / or each N atom is independently 14 N or 15 N.

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

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

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

[0022] In some embodiments, the compound of formula (A) is a compound shown in Table 1 or a pharmaceutically acceptable salt or ester thereof.

[0023] Table 1. GlcNBu derivatives

[0024] In some embodiments, the compounds of the present invention can be prodrugs of GlcNBu. In order not to be limited by existing theory, after administration, these compounds will be converted into GlcNBu in the body. Therefore, the compounds of the present invention can be used as prodrugs of GlcNBu. In this embodiment, compared with the direct administration of GlcNBu itself, the administration of the compounds of the present invention can increase the therapeutic efficacy of treating canine bone and joint diseases such as degenerative osteoarticular disease and / or arthritis. Compared with the administration of GlcNBu and / or some prodrugs of GlcNBu, the bioavailability, stability and / or metabolism of GlcNBu are increased in canines. Specifically including at least one of the following effects: improving the bioavailability of GlcNBu; increasing the area under the curve (AUC) of the GlcNBu concentration in blood or plasma; increasing the maximum drug concentration (C max ); increase the peak concentration time of GlcNBu (T max ); Improve the half-life of GlcNBu (t 1 / 2 ); improving the therapeutic biodistribution of GlcNBu; increasing the therapeutic level of GlcNBu in selected tissues; increasing the bioabsorption of GlcNBu; reducing the metabolism of GlcNBu; and reducing the side effects of GlcNBu.

[0025] The second aspect of the present 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 comprising a compound of formula (A) or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable carrier is provided, wherein the compound is not a derivative of N-acetylglucosamine.

[0026] Furthermore, the pharmaceutical composition of the present invention is a controlled-release agent, preferably an enteric-coated controlled-release agent.

[0027] Preferably, the pharmaceutical composition is suitable for oral administration.

[0028] In some embodiments, the pharmaceutical composition is suitable for administration by injection, including intramuscular injection, intraperitoneal injection, intraarticular injection or intravenous injection.

[0029] In other embodiments, the pharmaceutical composition is suitable for external use.

[0030] Specifically, the pharmaceutical composition may be in the form of a capsule, pill, tablet, powder, granule, lozenge, solution, ointment, cream or patch.

[0031] Furthermore, the capsule is a hard capsule, a soft capsule or a cachet.

[0032] Furthermore, the pills are sugar-coated pills.

[0033] Furthermore, the tablet is a lozenge.

[0034] Furthermore, the solution is in the form of an aqueous liquid suspension, a non-aqueous liquid suspension, an oil-in-water liquid emulsion, a water-in-oil liquid emulsion, a syrup, an elixir or a tincture.

[0035] Furthermore, the paste is an ointment.

[0036] Furthermore, the patch is a Babu patch.

[0037] The third aspect of the present application provides use of the compound or pharmaceutical composition of the present invention in the preparation of a medicament for treating and / or preventing bone or joint diseases in mammals, especially canines.

[0038] In one aspect, the methods provided herein are used for treating bone and / or joint diseases including, but not limited to, osteoporosis, osteopenia, and / or joint diseases.

[0039] In another aspect, the joint disease is osteoarthritis (including hip dysplasia, knee arthritis, osteochondrosis, hypertrophic arthritis), inflammatory arthritis (including rheumatoid arthritis or psoriatic arthritis), degenerative arthritis, traumatic arthritis or dysplastic arthritis.

[0040] Preferably, the present invention provides a method for preventing or treating degenerative joint disease in canines, comprising administering to a subject an effective amount of a compound and / or pharmaceutical composition described herein. Degenerative joint disease is a disease that causes progressive loss of articular cartilage and subchondral bone. Symptoms may include joint pain, tenderness, stiffness, locking, and sometimes effusion. Most commonly, degenerative joint disease is referred to as osteoarthritis, although it may encompass other diseases that include degenerative processes that often cause pain.

[0041] Degenerative joint disorders are understood in the present invention to be conditions or symptoms occurring in a subject dog suffering from a degenerative joint disease, such as lameness in an animal suffering from osteoarthritis in the legs.

[0042] In some embodiments, administration of a compound of the present invention or a pharmaceutical composition thereof can increase the bioavailability of GlcNBu in canines, the AUC of GlcNBu in blood or plasma, the C of GlcNBu, and the like, compared to administration of GlcNBu itself. max 、GlcNBu T max , improve the t of GlcNBu 1 / 2 , therapeutic biodistribution of GlcNBu and / or in vivo bioabsorption of GlcNBu.

[0043] In other embodiments, administration of a compound of the present invention or a pharmaceutical composition thereof can increase the bioavailability of GlcNBu, the AUC of GlcNBu in blood or plasma, the C of GlcNBu, and the D of GlcNBu in canines compared to administration of some disclosed prodrugs of GlcNBu. max 、GlcNBu T max , improve the t of GlcNBu 1 / 2 , therapeutic biodistribution of GlcNBu and / or in vivo bioabsorption of GlcNBu.

[0044] In some embodiments, the effective concentration of GlcNBu in a selected tissue of a canine patient is increased following administration of a compound of the present invention or a pharmaceutical composition thereof, compared to administration of GlcNBu itself.

[0045] In other embodiments, administration of a compound of the present invention or a pharmaceutical composition thereof results in an increased effective concentration of GlcNBu in a selected tissue of a canine patient, compared to administration of certain disclosed prodrugs of GlcNBu.

[0046] In some embodiments, administration of a compound of the present invention or a pharmaceutical composition thereof can reduce the metabolism of GlcNBu in vivo compared to administration of GlcNBu itself.

[0047] In other embodiments, administration of a compound of the present invention or a pharmaceutical composition thereof can reduce the metabolism of GlcNBu in vivo compared to administration of certain disclosed prodrugs of GlcNBu.

[0048] In some embodiments, administration of a compound of the present invention or a pharmaceutical composition thereof reduces the side effects of GlcNBu in vivo compared to administration of GlcNBu itself.

[0049] In other embodiments, administration of the compounds of the present invention or pharmaceutical compositions thereof can reduce the side effects of GlcNBu in vivo compared to administration of certain disclosed prodrugs of GlcNBu.

[0050] In some embodiments, administration of a compound of the present invention or a pharmaceutical composition thereof enhances glucosaminoglycan production in a canine subject compared to administration of GlcNBu itself.

[0051] In other embodiments, administration of a compound of the present invention or a pharmaceutical composition thereof enhances glycosaminoglycan production in a canine subject compared to administration of certain disclosed prodrugs of GlcNBu.

[0052] In a fourth aspect of the present application, a treatment kit comprising one or more compounds or pharmaceutical compositions of the present invention is provided. The treatment kit may further comprise instructions for use, for example, specifically describing how to use the treatment kit to treat or prevent bone or joint disorders such as osteoporosis, osteopenia, or arthritis.

[0053] Through the present invention, at least some of the defects in the prior art can be improved, the bioavailability and stability in canines can be improved and / or the metabolism of the compound can be reduced, side effects can be reduced, the bioavailability of the active ingredients of the drug can be increased, and the effect of treating canine bone or joint diseases can be better achieved. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] In order to better understand the present invention and to more clearly show how it may be implemented, further description will now be given by way of example with reference to the accompanying drawings, which illustrate various aspects and features of embodiments according to the present invention, in which:

[0055] Figure 1 is a curve showing the average concentration of GLcNBu in plasma relative to time (drug-time curve) after oral administration of Compound 2 and GlcNBu at equimolar doses; experimental animals were beagle dogs.

[0056] Figure 2 is a curve showing the average concentration of GLcNBu in plasma relative to time (drug-time curve) after oral administration of Compound 3 and GlcNBu at equimolar doses; experimental animals are beagle dogs.

[0057] FIG3 is a comparison of the mean plasma GLcNBu concentration versus time curves after oral administration of equimolar doses of compounds 1, 2, 3 and 4 of the present invention; experimental animals: beagle dogs. DETAILED DESCRIPTION

[0058] definition

[0059] For convenience, the meanings of certain terms and phrases used in the present invention are provided below. Unless otherwise specified, all technical and scientific terms used in the present invention have the same meanings as commonly understood by those skilled in the art in the art to which the present invention pertains.

[0060] When used in conjunction with the term "comprising" in the claims and / or the specification, the use of the quantifier "a" or "an" can mean "one or an," but it also means "one or more," "at least one," and "one or more than one." Similarly, the term "another" can mean at least a second or more. Furthermore, the singular form "a" or "an" can refer to both the singular and the plural.

[0061] As used in this specification and claims, the words "comprising" (and any form of comprising, such as "including" and "comprising"), "having" (and any form of having, "having", "including" and "containing") are inclusive and open-ended and do not exclude additional unrecited elements, steps or processes.

[0062] The terms "about" or "approximately" are used to indicate a value that includes error due to the equipment and method used to determine the value.

[0063] The term "derivative" used in the present invention should be understood as another compound that is similar in structure but different in some minor structures.

[0064] This specification refers to many chemical terms and abbreviations used by those skilled in the art. However, for the sake of clarity and consistency, definitions of selected terms are provided.

[0065] As used herein, the term "amino acid" generally refers to an organic compound that contains both a carboxylic acid group and an amine group. The term "amino acid" includes both "natural" and "unnatural" amino acids. Additionally, the term amino acid includes O-alkylated and N-alkylated amino acids, as well as amino acids with nitrogen-, sulfur-, or oxygen-containing side chains (e.g., Lys, Cys, or Ser), wherein the nitrogen, sulfur, or oxygen atom may or may not be acylated or alkylated. Amino acids may be L-amino acids, D-amino acids, or mixed L- and D-amino acids, including, but not limited to, racemic mixtures.

[0066] As used herein, the term "natural amino acid" and equivalent expressions refer to L-amino acids or non-protein-forming amino acids 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.

[0067] A residue is the main part of a molecule after a certain group is removed, such as an amino acid residue (such as the structure H2NCH2CO-, i.e., a glycyl group, which is the part after a hydroxyl group is removed from glycine).

[0068] Sometimes, an amino acid residue substituent is simply referred to as an amino acid group. When describing a series of substituents, the expression "the substituent is an amino acid" is equivalent to "the substituent is an amino acid residue."

[0069] It should be understood that the terms "substituted" or "substituted" as used herein include the implicit condition that such substitution, along with the change in the valence of the substituted atom and the substituent, produces a stable compound (e.g., the compound cannot spontaneously undergo rearrangement, cyclization, elimination, etc.). As used herein, the term "substituted" includes all permissible substituents of organic compounds.

[0070] Isotopic enrichment is a process in which a specific isotope is enriched (i.e., increased) by changing the relative abundance of the isotopes of a given element, and a corresponding reduction or depletion of another isotope. An isotopically enriched compound refers to one in which one or more specific elements are enriched in the form of isotopes that are not naturally abundant. The term "isotopically enriched element" as used in the present invention refers to one or more specific isotopes of a certain atom in a compound being increased (i.e., one or more specific isotopic elements are enriched or increased). Typically, in an isotopically enriched compound or derivative, a specific isotopic element at a specific position of the compound is enriched or increased. However, it should be understood that a compound can have two or more isotopic elements of an atom enriched or increased, including different isotopes of the same type of atom and respective isotopes of different types of atoms. In addition, an isotopically enriched compound can be an isotopically enriched mixed form, i.e., containing multiple specific isotopes or elements or both.

[0071] Typically, deuterium (D or 2 H) (its stable isotope with a mass about twice that of hydrogen), nitrogen-15 ( 15 N), carbon-13( 13 C), oxygen-18( 18 O) and oxygen-17( 17 The natural abundance of isotopes (O) is 0.016%, 0.37%, 1.11%, 0.204% and 0.037% respectively. "Isotopically enriched" compounds or derivatives used in the present invention have isotopic levels higher than this natural abundance. The level of isotopic enrichment depends on the natural abundance of the specific isotope itself. In some embodiments, the isotopic enrichment level of the compound or element in the compound can be about 1 to about 100 mole percent (%), such as 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 isotopic enrichment level of the isotopically enriched compounds of the present invention is about 5% or higher, or about 10% or more. In another embodiment, the isotopic enrichment level of the isotopically enriched compounds of the present invention is about 20% or higher, or about 50% or more. In another embodiment, the isotopic enrichment level of the isotopic enriched compounds of the present invention is about 75% or more, or about 90% or more. In another embodiment, the isotopic enrichment level of the isotopic enriched compounds of the present invention is about 95% or more, or 100%. In another embodiment, the isotopic enrichment level of the isotopic enriched compounds of the present invention is about 98% to 100%.

[0072] It is noteworthy 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 chemical, pharmacokinetic and therapeutic effects, with the goal of improving the compound's therapeutic efficacy, therapeutic biodistribution, bioavailability, metabolism, stability and / or pharmacokinetics.

[0073] As used herein, the term "natural abundance element" refers to the element by atomic mass that is most abundant in nature. For example, the natural abundance of hydrogen is 1 H, the natural abundance of nitrogen is 14 N; the natural abundance of oxygen is 16 O, the natural abundance of carbon is 12 C, etc. A "non-isotopically enriched" compound is one in which all the atoms or elements in the compound are isotopes of natural abundance, i.e., the atomic mass of all the atoms or elements is the most abundant in nature.

[0074] Unless otherwise specified, the compounds and compositions described in the present invention are non-isotopically enriched compounds, or compounds enriched in one or more isotopes.

[0075] A "pharmaceutically acceptable salt" of a compound refers to a salt of a compound that is pharmaceutically acceptable. A desired salt of a compound (basic, acidic, or charged functional group) retains or improves the biological activity and properties of the parent compound as defined herein and is not biologically undesirable. Pharmaceutically acceptable salts may be those described by Berge et al. in "Pharmaceutical Salts," J. Pharm. Sci. 66, 1-19 (1977). Examples include, but are not limited to:

[0076] (1) Salts formed by adding an acid to a basic or positively charged functional group. 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, pivalic 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, laurylsulfonic acid, oleic acid, palmitic acid, stearic acid, lauric acid, pamoic acid (pamoic acid), pamoic acid, pantothenic acid, lactobionic acid, alginic acid, galactaric acid, galacturonic acid, gluconic acid, glucoheptonic acid, glutamic acid, naphthoic acid, hydroxynaphthoic acid, salicylic acid, ascorbic acid, stearic acid, muconic acid, etc.

[0077] (2) When acidic protons are present in the parent compound or are replaced by metal ions, a base may be added to obtain a salt. The metal ions include alkaline metal ions (e.g., lithium, sodium, potassium), alkaline earth metal ions (magnesium, calcium, barium), or other metal ions such as aluminum, zinc, iron, etc. Organic bases include, but are not limited to, N,N'-dibenzylethylenediamine, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, piperazine, chloroprocaine, procaine, choline, lysine, etc.

[0078] Pharmaceutically acceptable salts can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods. Typically, such salts are prepared by reacting a compound (free acid or base) with an equistoichiometric amount of a base or acid in water, an organic solvent, or a mixture of the two. Salts can be prepared in situ during the final isolation or purification of the pharmaceutical agent, or by reacting a purified compound of the invention in its free acid or base form with the desired corresponding base or acid and isolating the salt thus formed. The term "pharmaceutically acceptable salt" also includes zwitterionic compounds containing a cationic group covalently bonded to an anionic group, which are referred to as "inner salts." The compounds of the invention encompass all acid, salt, base, and other ionic and non-ionic forms. For example, if a compound of the invention is an acid, the salt form of the compound is also encompassed. Similarly, if a compound of the invention is a salt, the acid and / or base forms of the compound are also encompassed. In some embodiments, the present invention relates to pharmaceutically acceptable salts of compounds. According to the understanding of those skilled in the art, various salts (such as 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 and organic acids and bases). For example, for a compound containing basic nitrogen, its salt can be prepared from a pharmaceutically acceptable non-toxic acid (including inorganic acids and organic acids). Pharmaceutically acceptable acids suitable for the present invention include but are not limited to acetic acid, benzenesulfonic acid (benzenesulfonate), benzoic acid, camphorsulfonic acid, citric acid, ethylenesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, etc. When the compound contains an acidic side chain, pharmaceutically acceptable bases suitable for use in the present invention include, but are not limited to, metal salts made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc, or organic salts made from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine.

[0079] The "pharmaceutically acceptable ester" of a compound refers to a pharmaceutically acceptable ester of the compound, which is substantially non-toxic to organisms and is hydrolyzed in vivo to form the compound of the present invention or a salt thereof.

[0080] In some embodiments, pharmaceutically acceptable "esters" of the compounds of the present invention include but are not limited to esters obtained by reacting at least one hydroxyl group of the compounds of the present invention with a group of the general formula R'COOH (carboxylic acid) or a group of the general formula R'SO3H (sulfonic acid).

[0081] As used herein, the term "AUC" is the area under the curve that represents the concentration in a biological sample of a subject as a function of time after administration of a compound to the subject. Examples of biological samples include, but are not limited to, biological fluids such as plasma, blood, cerebrospinal fluid (CSF) and saliva, organ homogenates such as brain and liver homogenates, and the like. AUC can be determined by measuring the concentration of the compound in the biological sample at various time intervals using liquid chromatography-tandem mass spectrometry (LC / MS / MS) and calculating the area under the concentration versus time period. Methods for calculating AUC from drug concentration-time curves are well known in the art. In connection with the present disclosure, the AUC of GlcNBu can be determined by measuring the concentration of GlcNBu in plasma, blood, or tissue homogenates of a subject following oral administration of a compound described herein.

[0082] As used herein, the term "bioavailability" refers to the rate and amount of drug that reaches the systemic circulation of a subject after administration of a drug or prodrug to a patient and can be determined by, for example, evaluating the plasma or blood concentration versus time profile of the compound. Parameters used to characterize the plasma or blood concentration versus time curve include the area under the curve (AUC), the time to peak concentration (T max ) and maximum drug concentration (C max ). The term “C max ” refers to the maximum concentration of a compound in a biological sample of a subject after a certain dose of the compound is administered to the subject. The term “T max " is the maximum concentration (C max ) time. 1 / 2 " is the terminal elimination half-life of the compound in the biological samples of the test dogs after a certain dose of the compound is administered to the test dogs. Bioavailability is usually expressed as F (%), which refers to the percentage of the AUC of the compound under a specific administration route (such as oral) relative to the AUC of the compound after intravenous (IV) administration.

[0083] When the compound of the present invention is used as a prodrug of GlcNBu, the area under the curve (AUC), peak concentration time (T max ), maximum drug concentration (Cmax ) and “t 1 / 2 " refers to the area under the curve (AUC) of GlcNBu and the time to peak concentration (T max ), maximum drug concentration (C max ) and “t 1 / 2 ”.

[0084] As used herein, the term "bioequivalence" refers to the equivalence of the rate and extent of absorption of a pharmaceutical agent (e.g., a compound) after administration of the same dose of the pharmaceutical agent to a patient. As used herein, two plasma or blood concentration profiles are bioequivalent if the 90% confidence interval of the mean response rate of the two profiles is within the limits of 0.8 and 1.25. The mean response includes at least one characteristic parameter of the profile, such as C max , T max and AUC.

[0085] As used herein, the term "effective amount" refers to the amount or amount of a compound that provides the desired effect in a patient being diagnosed or treated, following single or multiple dose administration. An effective amount can be readily determined by the attending physician or diagnostician using known techniques and by observing results obtained under similar circumstances. In determining the effective amount or dosage of a compound, the attending physician or diagnostician considers many factors, including, but not limited to, the weight or size, age, and general health of the patient, the specific disease involved, the extent or severity of the disease, the response of the individual patient, the specific compound administered, the bioavailability characteristics of the administered formulation, the selected dosing regimen, the use of concurrent medications, and related circumstances.

[0086] As used herein, the term "pharmaceutically acceptable" refers to drugs, pharmaceuticals, inert ingredients, etc., which are suitable for use in contact with human and animal cells or tissues without undue toxicity, incompatibility, instability, irritation, allergic response, etc., commensurate with a reasonable benefit / risk ratio. It generally refers to compounds, compositions, and formulations approved or approvable by a regulatory agency of a federal or state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.

[0087] "Pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient, vehicle or carrier with which a compound is administered. The terms "pharmaceutically acceptable carrier" and "pharmaceutically acceptable carrier" are used interchangeably herein.

[0088] A "pharmaceutical composition" refers to a composition comprising a compound described herein and at least one pharmaceutically acceptable carrier, diluent, adjuvant, excipient or vehicle such as a preservative, filler, disintegrant, wetting agent, emulsifier, suspending agent, sweetener, flavoring agent, aromatic, antibacterial agent, antifungal agent, lubricant, dispersant, etc., depending on the mode of administration and dosage form.

[0089] "Prevent" means at least reducing the likelihood of acquiring (or susceptibility to) a disease or disorder (i.e., preventing at least one clinical symptom of the disease from developing in a patient who may be exposed to or susceptible to the disease but does not yet experience or display symptoms of the disease).

[0090] In some embodiments, the term "treating" as used herein refers to any disease or condition that is treated to improve at least one disease or condition (i.e., halt or reduce the development of the disease or at least one of its clinical symptoms). In certain embodiments, "treating" refers to improving a physical parameter of a patient that may or may not be discernible to the patient. In certain embodiments, "treating" refers to inhibiting a disease or condition physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of a physical parameter), or both. In some embodiments, "treating" refers to improving the quality of life or reducing the symptoms or side effects of a bone or joint disease, such as osteoporosis or arthritis, in a dog in need thereof. A "therapeutically effective amount" refers to the amount of a compound that, when administered to a dog to treat or prevent a disease, is sufficient to achieve treatment or prevention of the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc. of the dog to be treated or prevented. As used herein, the term "therapeutically effective amount" refers to an amount of a compound or composition sufficient to prevent, treat, inhibit, reduce, ameliorate, or eliminate one or more causes, symptoms, or complications of a bone or joint disease, such as osteoporosis, osteopenia, or arthritis. In certain embodiments, the desired therapeutic effect is to achieve one or more of the following in a subject dog: enhanced cartilage formation; enhanced chondrocyte proliferation or growth; reduced joint stiffness; increased mobility or reduced mobility restriction; enhanced glycosaminoglycan production; increased bone mineral density (BMD); improved bone microarchitecture and / or bone connectivity; and reduced fracture risk.

[0091] "Therapeutic effectiveness" refers to the ability of a compound or composition to provide a desired therapeutic effect. As used herein, the term "increasing therapeutic effect" refers to increasing the therapeutic effect provided by a particular active therapeutic agent. In certain embodiments, "increasing therapeutic effect" refers to improving the pharmacokinetics of a therapeutic agent, such as obtaining one or more target pharmacokinetic parameters such that the ability of the therapeutic agent to achieve the desired therapeutic effect is improved or enhanced. In some embodiments, "increasing therapeutic effectiveness" means increasing one or more of the following: the bioavailability of GlcNBu; the AUC of GlcNBu in blood or plasma; the C of GlcNBu; max ; T of GlcNBu max ; The half-life of GlcNBu (t 1 / 2 ); biodistribution of GlcNBu; levels of GlcNBu in selected tissues; and / or bioabsorption of GlcNBu; in one subject, compared to administration of GlcNBu by itself. In some embodiments, "increasing therapeutic effectiveness" means reducing one or more of the following: metabolism of GlcNBu; and side effects of GlcNBu; in one subject, compared to administration of GlcNBu by itself. In some embodiments, "increasing therapeutic effectiveness" means reducing the dose and / or frequency of administration of a compound or composition sufficient to provide the desired therapeutic effect in a subject dog.

[0092] The term "canine subject" includes canines, particularly dogs.

[0093] As used herein, the term "prodrug" and equivalent expressions refer to a form of a drug that can be directly or indirectly converted into an active compound in vitro or in vivo (see, for example, RB Silverman, 1992, "The Organic Chemistry of Drug Design and Drug Action", Academic Press, Chap. 8; Bundgaard, Hans; Editor. Neth. (1985), "Design of Prodrugs". 360 pp. Elsevier, Amsterdam; Stella, V.; Borchardt, R.; Hageman, M.; Oliyai, R.; Maag, H.; Tilley, J. (Eds.) (2007), "Prodrugs: Challenges and Rewards", XVIII, 1470 p. Springer). Prodrugs can be used to alter biodistribution (e.g., allowing an agent to access a protease reaction site that is not normally accessible) or the pharmacokinetics of a particular agent. A variety of groups can be used to modify a compound to form a prodrug, such as esters, ethers, phosphates, and the like. When the prodrug is administered to a subject, the group is enzymatically or non-enzymatically cleaved, reduced, oxidized or hydrolyzed, or otherwise released to release the active compound. As encompassed by the present invention, "prodrug" refers to its pharmaceutically acceptable salts or pharmaceutically acceptable solvates, as well as crystalline forms of any of the above drugs. Prodrugs are often (but not necessarily) pharmacologically inactive before being converted to their active form.

[0094] Preparation method

[0095] The compounds of the present invention can be prepared using methods known in the art, such as starting with the corresponding glucosamine and performing substitutions on the corresponding hydroxyl groups. For example, the compound of Formula A defined above can generally be prepared starting with N-butyryl-D-glucosamine by performing an esterification reaction on the hydroxyl group at position 1. For substituents containing amino and / or hydroxy groups, the amino and / or hydroxy groups can be protected prior to the reaction, for example, using the most common Boc group, to avoid unwanted side reactions. After the reaction, the protection is removed to further prepare a pharmaceutically acceptable salt, such as a hydrochloride.

[0096] These preparation methods are conventional methods in the art, and it is believed that those skilled in the art can select an appropriate synthesis route according to actual needs. Therefore, they will not be described in detail here.

[0097] Pharmaceutical composition

[0098] In one embodiment, the pharmaceutical composition of the present invention comprises any one of the compounds of formula A 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 the specific compound mentioned in the present invention (the compound in Table 1), or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In another embodiment, the pharmaceutical composition of the present invention comprises any one of the compounds of formula (A) defined above and the specific compound in Table 1, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, with the proviso that the compound is not an N-acetyl-glucosamine derivative.

[0099] The preparation of pharmaceutical compositions can be carried out by methods known in the art (e.g., with reference to Remington: The Science and Practice of Pharmacy, 20th Edition, 2000). For example, the compound and / or composition is combined with one or more pharmaceutical carrier materials and / or additives (or auxiliary substances) in solid or liquid form, and with other active compounds having therapeutic or preventive effects (if necessary), to form a suitable mode of administration or dosage form, and then administered as a drug to canines. The preparation of the medicament can be added with many additives known in the art, such as fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, dispersants, preservatives, sweeteners, colorants, flavorings, fragrances, thickeners, diluents, buffers, solvents, solubilizers, agents for achieving a reservoir effect, salts for changing osmotic pressure, coating agents and / or antioxidants, etc.

[0100] As used herein, the term "pharmaceutically acceptable carrier" is intended to encompass any carrier, diluent, adjuvant, excipient, or vehicle described herein. Non-limiting examples of suspending agents include ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, and tragacanth gum, or mixtures thereof. Protection against the effects of microorganisms can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, and sorbic acid. Isotonic agents, such as sugars and sodium chloride, may also be added. Prolonged absorption of injectable drugs can be achieved by using agents that delay absorption, such as aluminum monostearate and gelatin. Non-limiting examples of suitable carriers, diluents, solvents, or vehicles include water, ethanol, polyols, and 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, alginic acid, and certain complex silicates. Non-limiting examples of lubricants include magnesium stearate, sodium lauryl sulfate, talc, and high molecular weight polyethylene glycols.

[0101] Pharmaceutically acceptable carriers may include any or all of physiologically acceptable solvents, dispersion media, coatings, antibacterial agents, antifungal agents, isotonic agents, absorption delaying 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 topical administration or administration by inhalation. Pharmaceutically acceptable carriers may include sterile aqueous solutions or dispersions and sterile powders that can be used for the extemporaneous preparation of sterile injectable solutions or dispersions. Such media and reagents are disclosed in the art for pharmaceutically active substances. Except for some conventional media or reagents that are incompatible with the active compound, the pharmaceutical composition of the present invention can achieve expectations.

[0102] The pharmaceutical compositions of the present invention can be administered orally, for example, in the form of pills (such as dragees), tablets (such as lacquer tablets, sugar-coated tablets, lozenges), powders, lozenges, granules, hard and soft (gelatin) capsules, cachets, aqueous solutions, alcoholic (or oily) solutions, syrups, emulsions, suspensions, oil-in-water liquid emulsions, water-in-oil liquid emulsions, elixirs, or syrups. Or by rectal administration, for example in the form of suppositories. It can also be administered parenterally, for example, by injection or infusion for subcutaneous, intramuscular or intravenous administration. Other suitable modes of administration are intradermal or transdermal, for example, in the form of ointments (such as ointments, creams), creams, patches (such as cataplasms), tinctures, sprays or transdermal therapeutic systems. Or it can be administered by inhalation in the form of nasal sprays or aerosol mixtures. Or it can be administered by microcapsules, implants or wafers.

[0103] In some embodiments, the pharmaceutical composition may or may not be enteric-coated. In some embodiments, the pharmaceutical composition is formulated into a formulation capable of controlling drug release, such as delayed release or extended release.

[0104] In a further embodiment, the compounds and compositions thereof can be formulated into a multi-dose form, i.e., in the form of a multi-particulate dosage form (e.g., a hard gelatin capsule or a conventional tablet prepared using a rotary tablet press), comprising one or more beads or mini-tablets for oral administration to a patient. Conventional tablets disperse rapidly after entering the stomach. One or more coated beads or mini-tablets can be compressed into corresponding tablets together with appropriate excipients (e.g., a binder, a diluent / filler, and a disintegrant for conventional tablets, etc.).

[0105] Tablets, pills, beads or mini-tablets of a compound or composition thereof may be coated or otherwise compounded to provide controlled drug release (including delayed release or extended release) or to protect against the acidic media of the stomach. For example, a tablet or pill may comprise an inner dose and an outer 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 of the inner dose.

[0106] In certain embodiments, the layer may comprise at least one enteric polymer. In other embodiments, the layer may comprise a combination of at least one enteric polymer and at least one water-insoluble polymer. In other embodiments, the layer may comprise a combination of at least one enteric polymer and at least one water-soluble polymer. In other embodiments, the layer may comprise a combination of at least one enteric polymer and a pore-forming agent.

[0107] In certain embodiments, the layer may comprise at least one water-insoluble polymer. In other embodiments, the layer may comprise a combination of at least one water-insoluble polymer and at least one water-soluble polymer. In other embodiments, the layer may comprise a combination of at least one water-insoluble polymer and a pore-forming agent.

[0108] Representative examples of water-soluble polymers include polyvinylpyrrolidone (PVP), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), polyethylene glycol, and the like.

[0109] 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 methacrylic acid-methyl methacrylate copolymers, and shellac. These polymers can be used as dry powders or aqueous dispersions. Some commercially available materials include methacrylic acid 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 phthalate aqueous dispersion) manufactured by FMC Corp. and Aqoat (hydroxypropyl methylcellulose acetate succinate aqueous dispersion) manufactured by Shin Etsu KK.

[0110] Representative examples of water-insoluble polymers include ethylcellulose, polyvinyl acetate (e.g., Kollicoat SR#30D manufactured by BASF), cellulose acetate, cellulose acetate butyrate, neutral copolymers based on ethyl acrylate and methyl methacrylate, copolymers of acrylic acid and methacrylate with quaternary ammonium salt groups (e.g., Eudragit NE, RS and RS30D, RL or RL30D, etc.).

[0111] Any above-mentioned polymer can be plasticized with one or more pharmaceutically acceptable plasticizers.The representative example of plasticizer comprises compound or its mixture such as triacetin, tributyl citrate, triethyl citrate, acetyl tri-n-butyl citrate, diethyl phthalate, castor oil, dibutyl sebacate, acetylated monoglyceride.When using plasticizer, plasticizer can account for approximately 3 to 30% of polymer weight, is usually about 10 to 25% of weight.The type of plasticizer and content thereof depend on the character (for example, based on aqueous or solvent, based on character such as solution or dispersion and total solids) of polymer or multiple polymers and coating system.

[0112] Pharmaceutical compositions must generally be sterile and stable under manufacturing and storage conditions. The composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable for high concentration drugs. The solvent or dispersion medium of the carrier can contain, for example, water, ethanol, polyols (such as glycerol, propylene glycol, and liquid polyethylene glycol, etc.) and suitable mixtures thereof. Appropriate fluidity can be achieved by using a coating (such as lecithin) and adding a surfactant to the dispersion system to maintain the desired particle size. In many cases, isotonic agents such as sugars, polyols such as mannitol, sorbitol, or sodium chloride can be added to the composition. By adding an agent that delays absorption (such as monostearate and gelatin) to the composition, the purpose of extending the absorption of the injected composition can be experimentally achieved. In addition, the compound can be made into a timed-release preparation, for example, by adding a polymer that can slowly release it to the composition. The compound can be prepared by adding a carrier that prevents rapid release, such as a controlled-release preparation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid, and polylactic acid, polyglycolic acid copolymers (PLG).

[0113] 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 the active compound, such as any of the compounds of formula (A), to a solvent, and sterilizing by filtration with one or a combination of the ingredients listed above, as desired. Typically, dispersions can be prepared by adding the active compound to a dispersion medium containing a sterile carrier and the ingredients listed above. When preparing sterile powders from sterile injectable solutions, a common method of preparation is to add a powder containing the active ingredient produced by 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.

[0114] For ease of administration and uniformity of dosage, it is generally advantageous to formulate parenteral compositions in dosage unit form. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for canines, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier. The specifications of the dosage unit forms of the present invention can vary and are dictated by and directly dependent upon (a) the unique characteristics of the therapeutic compound and the unique therapeutic effect to be achieved, and (b) the limitations inherent in formulating such therapeutic compounds. Dosage is discussed further below.

[0115] In some embodiments, the pharmaceutical composition comprises an effective amount of the compound and / or combination thereof and a pharmaceutically acceptable carrier.

[0116] In one embodiment, provided is a pharmaceutical composition for treating or preventing a bone or joint disorder comprising a compound described herein or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable carrier.

[0117] In one embodiment, a pharmaceutical composition for treating or preventing osteoporosis is provided, comprising a compound as 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 as described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0118] In some embodiments, when the compounds and treatment methods of the present invention are administered to a treated group, there is an acceptable difference between the treatment or prevention methods of the present invention and a placebo or historical control group.

[0119] It should be understood that the choice of one or more active compounds and / or compositions and their dosages will depend on the individual's individual circumstances (generally, the optimal effect should be achieved for the individual's circumstances). Administration and dosing regimens are within the skill of those skilled in the art, and appropriate dosages depend on many factors, including the level of knowledge of the ordinarily skilled 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, administration and the route of administration may depend on the subject's condition and its severity, as well as the sex, age, weight, and individual responsiveness of the animal being treated, the duration of action 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 therapeutically active substance.

[0120] Therefore, the dosage of the 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, diet of the test dog. The time of administration and route of administration, excretion rate and any applicable drug combination. The effect of the compound on the subject as desired by the physician. The properties of the compound administered (e.g., bioavailability, stability, efficacy, toxicity, etc.). A reasonable dose determined by those generally recognized in the art. When administering one or more compounds or compositions described herein to canines, the physician may first prescribe a relatively low dose and then increase the dose until an appropriate response is obtained.

[0121] Each compound involved in the present invention is not particularly limited for the dosage of compositions. Example doses include milligrams or micrograms of compound / kg patient or sample weight (for example, 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 doses include about 5-500mg, about 25-300mg, about 25-200mg, about 50-150mg or about 50mg, about 100mg, about 150mg, about 200mg, about 250mg, 500mg, about 1000mg, about 2000mg and about 3000mg, for example, daily or twice daily lower or higher dosage.

[0122] In some embodiments, the oral dose for adult dogs is generally 0.005 mg to 10 g / day. A certain amount (such a dose or a multiple thereof is an effective dose) of the compound (e.g., Formula A) can be conveniently contained in a tablet or other form. For example, 5 mg to 500 mg is contained, typically about 10 mg to 200 mg. The dosage unit (e.g., oral dosage unit) of the compound can 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, 18 mg, 20 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg g, 18 mg, 19 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, about 1000 mg, about 2000 mg, and about 3000 mg).

[0123] In some embodiments, the oral dosage of the compound generally 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.

[0124] The compounds and compositions of the present invention are applied to the treated dogs by known methods and dosages to achieve the desired goal within an effective time period. The dosage regimen can be adjusted as needed to achieve the best therapeutic effect. For example, the dose can be divided into multiple doses per day, or the dose can be reduced proportionally according to the emergency treatment situation. In some embodiments, the treated dogs can prevent or treat diseases of the bones or joints such as osteoporosis and arthritis under the action of an effective dose of the compound or composition. In addition, the compound or composition can be administered by any suitable route or mode, such as, but not limited to, oral, parenteral, intravenous, intraperitoneal, intramuscular, sublingual, topical or intranasal administration, inhalation, transdermal or patch methods commonly used in the art.

[0125] Compound involved in the present invention and composition can be administered once a day, twice, three times or four times by any reasonable way mentioned above.In addition, in some embodiments, the use of any compound of the present invention or treatment (according to the difference of compound structure) can continue for several weeks.Such as conventional treatment can continue 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 another embodiment, the use of any compound of the present invention or treatment (according to the difference of compound structure) can continue for several months.Such as conventional treatment can continue 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 other embodiments, administration or treatment with any of the compounds described herein (depending on the structure of the compound) can continue indefinitely.

[0126] Treatment

[0127] In some embodiments, a method of treating or preventing a bone or joint disorder in a canine subject in need thereof is provided, comprising administering to the canine subject an effective amount of a compound GlcNBu prodrug described herein or a pharmaceutical composition thereof, for example, to prevent or treat degenerative bone and / or joint disease in the canine subject.

[0128] Various bone or joint diseases can be treated or prevented by methods provided by the invention, including but not limited to osteoporosis, osteopenia and / or arthritis. Many types of arthritis are known, and methods provided herein can be used to treat or prevent, including but not limited to osteoarthritis, inflammatory arthritis (such as rheumatoid arthritis, psoriatic arthritis, etc.), traumatic arthritis, degenerative arthritis and dysplasia arthritis.

[0129] In one embodiment, a method of enhancing glycosaminoglycan production in a canine subject is provided.

[0130] In some embodiments, a method is provided for increasing the therapeutic effectiveness of GlcNBu in a canine subject in need thereof, comprising administering to the canine subject an effective amount of a compound of the present invention or a pharmaceutical composition thereof that is a prodrug of GlcNBu, such that the therapeutic effect is increased compared to direct administration of GlcNBu.

[0131] In some embodiments, the compounds, GlcNBu prodrugs or pharmaceutical compositions provided herein are administered to achieve an increase in one or more of the following effects: bioavailability of GlcNBu; AUC of GlcNBu in blood or plasma; C of GlcNBu; max; T of GlcNBu max ; t of GlcNBu 1 / 2 ; GlcNBu therapeutic biodistribution; therapeutic levels of GlcNBu in selected tissues; and / or bioabsorption of GlcNBu in test dogs, particularly improved bioavailability of GlcNBu. In some embodiments, one or more of the following effects are achieved by administering a compound, GlcNBu prodrug, or pharmaceutical composition as provided herein: reduced metabolism compared to direct administration of GlcNBu; reduced side effects in test dogs compared to direct administration of GlcNBu.

[0132] In some embodiments, a method for improving the targeted pharmacokinetic parameters of GlcNBu in vivo is provided, comprising administering an effective amount of a compound GlcNBu prodrug described herein or a pharmaceutical composition thereof to a test dog, such that the target pharmacokinetic parameters of GlcNBu are obtained in the test dog. Non-limiting examples of targeted pharmacokinetic parameters include targeted bioavailability, AUC in blood or plasma, C max , T max , biodistribution, levels in selected tissues, half-life (t 1 / 2 ), bioabsorption and metabolism amount or rate. Pharmacokinetic parameters can be calculated using methods known in the art.

[0133] In some embodiments of the methods provided herein, the canine is a beagle, a golden retriever, a Labrador retriever, a Chow Chow, a Pekingese, a pug, a Teddy dog, etc., in particular a beagle.

[0134] Example

[0135] The present invention will be more readily understood by reference to the following examples, which are provided to illustrate the invention and are not to be construed as limiting the scope of the invention in any way.

[0136] Unless otherwise defined or the context clearly dictates 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 the invention belongs. It should be understood that any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention.

[0137] Preparation example:

[0138] Preparation of GlcNBu

[0139] 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. Then, butyric anhydride (73.4 g, 464 mmol, 1 eq) was added. The mixture was stirred at room temperature for 4-5 hours. 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 and twice with ethyl acetate and dried to obtain butyrylglucosamine (53 g, 45.8% yield). 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).

[0140] Compound a: Preparation of 4,6-di-O-butyryl-N-butyryl glucosamine (Comparative Example 1)

[0141] Step A: Disperse butyrylglucosamine (10.0 g, 40 mmol, 1 eq) in 200 mL of N,N-dimethylformamide (DMF). Add benzaldehyde dimethyl acetal (60.8 g, 400 mmol, 10 eq) and toluenesulfonic acid monohydrate (0.76 g, 4 mmol, 0.1 eq) with stirring. The reaction mixture is stirred at 50°C for 16 hours. Cool the reaction mixture to room temperature, pour it into 800 mL of water, and stir for 1 hour. Filter the mixture, wash the filter cake with 100 mL of water, then with 100 mL of petroleum ether, and dry it to obtain 4,6-O-benzylidene-N-butyrylglucosamine (8.0 g, 59.0% yield).

[0142] Step B: 4,6-O-Benzylidene-N-butyryl glucosamine (3.37 g, 10 mmol, 1 eq) and benzyl bromide (3.76 g, 22 mmol, 2.2 eq) were dispersed in 50 mL of DMF and cooled to -10°C under nitrogen. NaH (1.08 g, 27 mmol, 2.7 eq) was added portionwise with stirring, while maintaining the reaction temperature below 0°C. The mixture was then slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was poured into 300 mL of water, and the mixture was stirred for 1 hour. The filter cake was filtered and washed with 50 mL of water and then with 50 mL of petroleum ether. After drying, 1,3-di-O-benzyl-4,6-O-benzylidene-N-butyryl glucosamine (4.5 g, 87.1% yield) was obtained.

[0143] Step C: 1,3-di-O-benzyl-4,6-O-benzylidene-N-butyryl glucosamine (4.5 g, 8.7 mmol, 1 eq) was dispersed in 90 mL of dichloromethane (DCM). 1.5 mL of water and 18 mL of trifluoroacetic acid were added with stirring, and 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 and then with 50 mL of saturated sodium bicarbonate solution. The solvent was evaporated, and the residue was hot-slurried with petroleum ether and filtered to obtain 1,3-di-O-benzyl-N-butyryl glucosamine (3.2 g, 85.7% yield).

[0144] Step D: 1,3-di-O-benzyl-N-butyryl glucosamine (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 filter cake was filtered and washed with 50 mL of water and then with 50 mL of petroleum ether. After drying, 1,3-di-O-benzyl-4,6-di-O-butyryl-N-butyryl glucosamine (2.9 g, 87.8% yield) was obtained.

[0145] 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, and 15 mL of acetic acid was added. After hydrogen substitution, the mixture was stirred under a hydrogen atmosphere for 48 hours. The reaction mixture was filtered, the filtrate was dried, and the residue was purified by column chromatography (MeOH / DCM = 1 / 100 to 1 / 30) to obtain 4,6-di-O-butyryl-N-butyryl glucosamine (Comparative Example 1) (1.3 g, yield 65.6%). 1 H 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). 13C NMR(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.

[0146] Compound b: Preparation of 6-O-(3-cyclopentylpropionyl)-N-butyryl glucosamine (Comparative Example 2)

[0147] 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-butyryl glucosamine (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 spin-dried to dryness. The residue was purified by silica gel column chromatography (DCM:MeOH, 50:1) to afford 1,3-di-O-benzyl-6-(3-cyclopentylpropionyl)-N-butyryl glucosamine (2 g, 77.57% yield).

[0148] Step B: 1,3-Di-O-benzyl-6-(3-cyclopentylpropionyl)-N-butyramidoglucose (2 g, 3.61 mmol, 1 eq) was dispersed in a mixture 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, stirred at this temperature for 24 hours, and then filtered. The filtrate was dried, and the residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to obtain compound b (850 mg, 63.01% yield). 1H 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.

[0149] Compound c: Preparation of 6-O-decanoyl-N-butyryl glucosamine (Comparative Example 3)

[0150] Decanoic acid was used as the starting material, and the relevant synthesis steps were referred to 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),3.55-3.69(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). 13 C 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.

[0151] Compound 1: Preparation of 6-O-(L-leucyl)-N-butyryl glucosamine hydrochloride

[0152] 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. 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) were then added. After stirring at room temperature for 15 hours, the reaction mixture was added to 500 mL of water, resulting in the formation of a white solid. After filtration, the obtained solid was purified by silica gel column chromatography (MeOH / DCM, 0%-2%) to give 1,3-di-O-benzyl 6-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).

[0153] Step B: 1,3-di-O-benzyl 6-O-(N-Boc-L-leucyl)-N-butyryl glucosamine (14.5 g, 22.56 mmol, 1 eq) was dispersed in 30 mL of acetic acid and 150 mL of tetrahydrofuran, and Pd / C (14.5 g, 5%, 6.81 mmol, 0.3 eq) was added. The reaction was carried out at 40 ° C under a hydrogen environment for 15 h. The insoluble matter was removed by filtration. The filtrate was concentrated and dried to give 6-O-(N-Boc-L-leucyl)-N-butyryl glucosamine (10.35 g, yield 99.2%). 1H NMR (500 MHz, CD3OD) δ ppm 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).

[0154] 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 h. After concentration, DCM (30 mL) and water (25 mL) were added, the mixture was stirred, and the mixture was allowed to stand. The aqueous phase was separated and lyophilized to obtain compound 1 (8.1 g, 92.57% yield) as a pale yellow solid. 1 H NMR(500MHz,D2O)δppm5.09(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). 13C NMR(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.

[0155] Compound 2: Preparation of 6-O-(L-isoleucyl)-N-butyryl glucosamine hydrochloride

[0156] N-Boc-L-isoleucine was used as the starting material, and the relevant synthesis steps were referred to the synthesis of 6-O-(L-leucyl)-N-butyryl glucosamine hydrochloride. 1 H NMR(500MHz,D2O)δppm 0.76-0.98(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),2.14-2.2 2(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.

[0157] Compound 3: Preparation of 6-O-(L-alanyl)-N-butyryl glucosamine hydrochloride

[0158] N-Boc-L-alanine was used as the starting material, and the relevant synthesis steps were referred to 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)δppm12.59,15.12,18.95,37.52,37.93,48.77,53.84,56.37, 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.

[0159] Compound 4: Preparation of 6-O-(L-glycyl)-N-butyryl glucosamine hydrochloride

[0160] N-Boc-L-glycine was used as the starting material, and the relevant synthesis steps were referred to 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.

[0161] Test case: Pharmacokinetic study

[0162] General Methods for Pharmacokinetic Studies

[0163] Reagent Preparation: For intravenous injection, the solvent is normal saline. Based on the weight correction factor, add an appropriate amount of normal saline to the original compound bottle to prepare a high-concentration stock solution for formulation. Pipette the required amount of this stock solution into a suitable container, add normal saline to the volume, and vortex until completely dissolved to obtain a homogeneous, clear solution. Sterilize the prepared intravenous formulation using a 0.22μm microporous filter and store at room temperature until use. Intravenous formulations are prepared on the day of administration and analyzed. For oral gavage, use normal saline as the solvent. Pipette the required amount of this stock solution into a suitable container, add normal saline to the volume, and vortex / stir until the solution is visually homogeneous.

[0164] Animal husbandry and sampling: A total of 34 beagle dogs (Beijing Mas Biotechnology Co., Ltd.) were kept in an animal room with a relative humidity of 40%-70%, a temperature of 18-26°C, and 10-20 air changes per hour. The experimental animals were weighed on the day of administration and dosed according to their body weight. The administration methods were divided into oral gavage (PO) and injection (IV). Oral gavage administration is done by oral gavage. After administration, the gavage tube is flushed with about 6 ml (3 times the volume of the gavage tube) of solvent. All tubes must be consistent in size and length. There is no difference in the tubes used for each animal, and the volume of the flushing medium is consistent. Intravenous administration is done by slow injection (within 3 minutes) through the cephalic vein or saphenous vein. The blood vessels used for administration are not used for blood sample collection. The experimental animals are accurately weighed after administration, and the general condition and appearance of the animals are observed after administration.

[0165] The test compound is dissolved in a solvent, and its concentration is determined by the desired dose and the administration volume of the specific animal used by the compound. In the experiment, 4 beagle dogs were randomly selected in each administration group and divided into two groups, wherein 3 of them were randomly selected to be orally administered with the test compound, and 1 was injected, and different compounds were administered with the same equivalent. The measured dosing solution volume was applied to the animals (in oral and intravenous modes). After administering 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 into plasma samples using standard techniques. After LC-MS / MS analysis, the concentration of the test compound and GlcNBu in plasma was obtained.

[0166] Pharmacokinetic studies of compounds 1-4 and ac

[0167] Animal grouping: 4 beagles were randomly selected from each dosing group and divided into 2 groups, 3 in the gavage administration group and 1 in the injection administration group. Compounds 1-4 and ac were formulated into injections and oral preparations according to the above method, and each dosage form was administered at 0.04 mmol / kg and 0.24 mmol / kg, respectively. Specifically: Compound 1 was administered to the gavage administration group at an oral dose of 87.2 mg / kg, and was administered to the injection administration group at an injection dose of 14.5 mg / kg; Compound 2 was administered to the gavage administration group at an oral dose of 87.2 mg / kg, and was administered to the injection administration group at an injection dose of 14.5 mg / kg; Compound 3 was administered to the gavage administration group at an oral dose of 77.1 mg / kg, and was administered to the gavage administration group at an injection dose of 12.9 mg / kg; Compound 4 was administered to the gavage administration group at an oral dose of 73.7 mg / kg, and was administered to the injection administration group at an injection dose of 12 Compound a was administered orally to the injection group at a dose of 93.4 mg / kg, and was administered orally to the gavage group at a dose of 15.6 mg / kg. Compound b was administered orally to the gavage group at a dose of 90 mg / kg, and was administered orally to the injection group at a dose of 15 mg / kg. Compound c was administered orally to the gavage group at a dose of 97.1 mg / kg, and was administered orally to the injection group at a dose of 5 mg / kg (due to its poor solubility, this injection dose was used to maximize its solubility). Six beagle dogs were randomly selected, three of which received GlcNBu (60 mg / kg, 0.24 mmol / kg) by gavage, and three received GlcNBu (10 mg / kg, 0.04 mmol / kg) by injection as a positive control group. Blood was collected venously at predetermined time points before and after administration, and the samples were analyzed by LC / MS-MS to determine the GlcNBu concentration in plasma.

[0168] The results of the pharmacokinetic studies after administration of different compounds are shown in FIG1 to FIG3 .

[0169] Figure 1 shows the plasma GlcNBu-time concentration after oral administration of compound 2 and GlcNBu. In this figure, the curves marked with -■- and -◆- respectively represent the plasma GlcNBu concentrations after oral administration of GlcNBu (60 mg / kg) and compound 2 (87.2 mg / kg). The results show that compound 2 significantly improved plasma drug exposure, with the plasma GlcNBu concentration C max , and AUC were improved to a certain extent.

[0170] Figure 2 shows the plasma GlcNBu-time concentration after oral administration of compound 3 and GlcNBu. In this figure, the curves marked with -◆- and -■- represent the plasma GlcNBu concentration after oral administration of GlcNBu (60 mg / kg) and compound 3 (77.1 mg / kg), respectively. The results show that compound 3 improves plasma drug exposure relative to GlcNBu, wherein the plasma GlcNBu concentration C max , and AUC were improved to a certain extent.

[0171] FIG3 shows the curves of plasma GlcNBu concentration versus time measured in different oral administration examples of compounds 1-4 of the present invention.

[0172] Table 2 provides the results of the determination of all pharmacokinetic parameters of compounds 2, 3 and the positive control GlcNBu after oral administration.

[0173] Table 2. PK parameters of GlcNBu in blood after administration of compounds 2, 3 and positive control GlcNBu

[0174] AUC (0-8) : The area under the drug-time curve (0-8), that is, the area enclosed by the blood drug concentration curve on the time axis (0-∞) from the initial stage to 8 hours.

[0175] AUC (0-∞) : The area under the (0-∞) segment drug-time curve, that is, the area enclosed by the (0-∞) segment of the blood drug concentration curve on the time axis.

[0176] t 1 / 2 : Half-life. The larger the half-life value, the slower the drug elimination or distribution process.

[0177] T max : Peak time, that is, the time required to reach the peak drug concentration after administration.

[0178] C max : Peak drug concentration, that is, the highest blood drug concentration after administration.

[0179] As shown in Table 2, the PK parameters of compound 2 and compound 3 are 40%-50% higher in AUC than in GlcNBu. max and t 1 / 2 Compared with GlcNBu, it is improved by more than 20%.

[0180] Table 3 shows the results of bioavailability (F%) of compounds 1-4 and compounds ac after equimolar oral / intravenous administration.

[0181] Table 3. Administration of Compounds 1-4 and Compounds ac* After that, bioavailability parameters

[0182] *Compounds ac are comparative examples 1-3

[0183] As shown in Table 3, the bioavailability parameters of Compound 2 and Compound 3 when administered to dogs were significantly higher than those of the other compounds and Comparative Examples 1, 2, and 3. That is, when Compound 2 or Compound 3 was administered to dogs, the speed and amount of the drug reaching the systemic circulation of the treated dog were better than those of the comparative examples.

[0184] Although the present invention has been described in detail with reference to the embodiments of the present invention, these embodiments are provided to illustrate rather than limit the present invention. Other embodiments that can be obtained according to the principles of the present invention all fall within the scope defined by the claims of the present invention.

[0185] The contents of all documents and references cited herein are incorporated by reference in their entirety.

Claims

1. A compound represented by formula (A) or a pharmaceutically acceptable salt or ester thereof: in: R is an amino acid residue.

2. The compound according to claim 1, wherein The amino acid is a natural amino acid selected from the group consisting of valine, phenylalanine, histidine, isoleucine, leucine, alanine and glycine.

3. The compound according to claim 1 or 2, wherein The compound is an α-end isomer, a β-end isomer, or a mixture of α- and β-end isomers.

4. The compound according to any one of claims 1 to 3, wherein The R is an amino acid residue selected from the group consisting of L-leucine, L-isoleucine, L-glycine, and L-alanine. The structure of the compound is shown below:

5. The compound according to any one of claims 1 to 4, wherein C, H, O and N in the compound are each independently an element of natural abundance or an isotopically enriched element.

6. The compound according to claim 5, 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 independently 16 O. 17 O or 18 O, and / or each N atom is independently 14 N or 15 N.

7. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable carrier.

8. The pharmaceutical composition according to claim 7, wherein The pharmaceutical composition is in the form of capsules, pills, tablets, powders, granules, lozenges, solutions, ointments, creams or patches.

9. The pharmaceutical composition according to claim 8, wherein The pills are dragees.

10. The pharmaceutical composition according to claim 8, wherein The tablet is a lozenge.

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

12. The pharmaceutical composition according to claim 8, wherein The paste is an ointment.

13. The pharmaceutical composition according to claim 8, wherein The patch is a Babu patch.

14. The pharmaceutical composition according to claim 8, wherein The capsule is a hard capsule, a soft capsule or a cachet.

15. The pharmaceutical composition according to claim 8, wherein The pharmaceutical composition is a controlled release formulation.

16. The pharmaceutical composition according to claim 14, wherein The controlled-release agent is an enteric-coated controlled-release agent.

17. The pharmaceutical composition according to claim 7, wherein The pharmaceutical composition is suitable for oral administration.

18. The pharmaceutical composition according to claim 7, wherein The pharmaceutical composition is suitable for injection.

19. The pharmaceutical composition according to claim 18, wherein The pharmaceutical composition is suitable for intramuscular injection, intraperitoneal injection, joint cavity injection or intravenous injection.

20. The pharmaceutical composition according to claim 7, wherein The pharmaceutical composition is suitable for external use.

21. Use of a compound according to any one of claims 1 to 6 or a pharmaceutical composition according to any one of claims 7 to 20 for the preparation of a medicament for the treatment and / or prevention of bone and / or joint diseases in canines.

22. The use according to claim 21, wherein: The bone and / or joint disease is at least one selected from the group consisting of osteoporosis, osteopenia and arthritis.

23. The use according to claim 22, wherein: The arthritis is osteoarthritis, degenerative arthritis, inflammatory arthritis, traumatic arthritis or dysplastic arthritis.

24. The use according to claim 23, wherein the inflammatory arthritis is rheumatoid arthritis or psoriatic arthritis.

25. The use according to any one of claims 21 to 24, wherein: The canine is a dog.

26. A treatment kit comprising the compound of any one of claims 1-6 or the pharmaceutical composition of any one of claims 7-20 and instructions for use.

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