Compounds for treatment or prevention of gout

Abstract

The present invention provides a compound of formula (I): wherein R1 and R2 are different and selected from-H and-(C1-C6) alkyl, or a pharmaceutically acceptable salt thereof, for use in the prevention and / or treatment of a disease or disorder associated with the crystallization of monosodium urate monohydrate; r3 is selected from-H and = O; formula (II) is a double bond when R3 is-H, and Formula (II) is a single bond when R3 is = O. The invention also provides an in vitro method for eliminating and / or preventing formation of monosodium urate monohydrate crystals in a composition, and an in vitro use of a compound of formula (I) for eliminating and / or preventing formation of monosodium urate monohydrate crystals.

Description

[0001] This application claims priority to European patent application EP23382792.2, filed on July 28, 2023. Technical Field

[0002] This invention relates to the field of compounds capable of preventing the crystallization of monosodium urate monohydrate. The compounds of this invention are particularly suitable as medicines for the prevention or treatment of gout. Background Technology

[0003] Gout is a rheumatic disease that affects the joints (primarily the feet), although it often affects the hands as well. Gout causes intense pain and swelling, which is caused by the deposition of needle-like sodium urate (MSU) crystals. These crystals should not be confused with uric acid (UA) crystals, which cause kidney stones, as they have different structures and causes.

[0004] Uric acid is a product of purine metabolism. At pH 7.4 (as found in plasma and interstitial fluid), uric acid exists as urate ions, which combine with sodium ions to form MSU. Under normal conditions, the uric acid concentration in the blood does not exceed 6 mg / dL. At this concentration, MSU is soluble and does not form any type of crystal. However, some people produce high levels of uric acid, exceeding 6 mg / dL and even reaching 20 mg / dL, due to genetic factors associated with uric acid synthesis, or due to consuming diets particularly rich in purines (such as red meat, organ meats, sausages, fish, and shellfish) and alcoholic beverages.

[0005] When the uric acid concentration exceeds 6 mg / dL, it exceeds the solubility of MSU in the interstitial fluid. Therefore, this salt can crystallize in the form of fine MSU needles, which is what causes gout pain attacks.

[0006] Currently, treatment strategies for preventing MSU crystal formation primarily rely on a strict diet and the use of xanthine oxidoreductase (XOR) inhibitors, such as allopurinol and febuxostat, to lower serum urate levels, thereby reducing urate levels in synovial fluid. However, these methods are often ineffective, and XOR inhibitor drugs typically have significant side effects.

[0007] Therefore, despite the efforts made to date, there is still a need for compounds that can inhibit the formation of MSU crystals for the treatment of gout. Summary of the Invention

[0008] The inventors have discovered a specific group of compounds that possess a strong and specific ability to prevent the formation of MSU crystals.

[0009] As shown in the following examples, the inventors have discovered that methylxanthines of formula (I) can inhibit the formation of MSU crystals (see...). Figure 1 and 2 This is quite unexpected, because structure-related methylxanthines—such as theobromine, are known to prevent the formation of uric acid (UA) crystals—have not shown any effect on MSU crystallization (see [link to relevant documentation]). Figure 2 ).

[0010] Furthermore, the compounds of formula (I) have been previously used to treat other human diseases, such as myopia, without any reported side effects; therefore, they represent a safe treatment option.

[0011] In conclusion, based on the experimental data provided herein, it is clear that the compounds of the present invention can be used as safe and effective medicines for treating human diseases associated with MSU crystallization, such as gout.

[0012] Therefore, in a first aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for the prevention and / or treatment of diseases or disorders associated with uric acid monosodium hydrate crystallization, particularly gout.

[0013] Wherein, R1 and R2 are different and selected from -H and -(C1-C6)alkyl; R3 is selected from -H and =O; when R3 is -H... It is a double bond, when R3 is =0. It is a single key.

[0014] In a second aspect, the present invention provides an in vitro method for eliminating and / or preventing the formation of uric acid monosodium hydrate crystals in a composition containing uric acid, the method comprising contacting the composition with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0015] Wherein, R1 and R2 are different and selected from -H and -(C1-C6)alkyl; R3 is selected from -H and =O; when R3 is -H... It is a double bond, when R3 is =0. It is a single key.

[0016] In a third aspect, the present invention provides the in vitro use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the elimination and / or prevention of the formation of uric acid monosodium hydrate crystals.

[0017] Wherein, R1 and R2 are different and selected from -H and -(C1-C6)alkyl; R3 is selected from -H and =O; when R3 is -H... It is a double bond, when R3 is =0. It is a single key. Attached Figure Description

[0018] Figure 1 A 12-well plate image after 6 days (114 hours) of incubation. Each well contained an initial concentration of uric acid of 375 mg / L (2.23 mM), [Na+] of 400 mM, and 12 mM phosphate buffer at pH 7.4. Test compounds were added at a concentration of 0.3 mM.

[0019] Figure 2 The residual uric acid concentration in the solution after 4 days of incubation in the presence of each compound was measured. The initial concentrations of uric acid in each well were 375 mg / L (2.23 mM), [Na+] = 400 mM, and 12 mM phosphate buffer at pH 7.4. The concentration of the test compound added was 0.3 mM.

[0020] Figure 3 1. A 12-well plate after 3 days (72 hours) of incubation. Each well contains a solution of [UA] = 375 mg / L (2.23 mM), [Na+] = 400 mM, and 12 mM phosphate buffer at pH 7.4. The three wells in the first column are free of additives, the three wells in the second column contain 50 μM (8.3 mg / L) 7-methylxanthine, the three wells in the third column contain 100 μM (16.3 mg / L) 7-methylxanthine, and the three wells in the fourth column contain 150 μM (24.9 mg / L) 7-methylxanthine.

[0021] Figure 4 The residual uric acid concentration in the solution after incubation for 5 days (120 hours) in the presence of different concentrations of 7-methylxanthine or 3-methylxanthine. Each well contained uric acid with an initial concentration of 375 mg / L (2.23 mM), [Na+] = 400 mM, and 12 mM phosphate buffer at pH 7.4.

[0022] Figure 5 The residual uric acid concentration in the solution after incubation for 5 days (120 hours) in the presence of different mixtures of 7-methylxanthine and 3-methylxanthine. Each well had 12 mM phosphate buffer with an initial concentration of 375 mg / L (2.23 mM), [Na+] = 400 mM, and pH = 7.4.

[0023] Figure 6The residual uric acid concentration in the solution after incubation for 3 days (72 hours) in the presence of different concentrations of uric acid and the action of 7-methylxanthine was measured. Each well contained 12 mM phosphate buffer with an initial concentration of [Na+] = 400 mM and pH = 7.4.

[0024] Figure 7 The residual uric acid concentration in the solution after incubation for 4 days (96 hours) in the presence of different concentrations of uric acid and the action of 7-methylxanthine. Each well had an initial concentration of [Na+] = 400 mM and 12 mM phosphate buffer at pH = 7.4.

[0025] Figure 8 Photographs of 12-well plates containing different initial concentrations of uric acid, 120 hours after the start of the experiment, under conditions of absence and presence of different concentrations of 7-methylxanthine.

[0026] Figure 9 The residual uric acid concentration in the solution after incubation for 5 days (120 hours) in the presence of different concentrations of uric acid and the action of 7-methylxanthine was measured. Each well contained 12 mM phosphate buffer with an initial concentration of [Na+] = 400 mM and pH = 7.4.

[0027] Figure 10 The minimum concentration of 7-methylxanthine that completely prevents the formation of sodium urate crystals (C100) in the presence of different initial concentrations of uric acid. The solution also contains 12 mM phosphate buffer at [Na+] = 400 mM and pH = 7.4. Detailed Implementation

[0028] Unless otherwise stated, all terms used in this application shall be understood in their ordinary sense in the art. Other more specific definitions of terms used in this application are set forth below, and unless otherwise expressly provided to provide a broader definition, these definitions are intended to be consistent throughout the specification and claims.

[0029] As used in this article, the indefinite articles “a” and “one” are synonymous with “at least one” or “one or more”. Unless otherwise stated, the definite articles used in this article, such as “the”, also include the plural form of the noun.

[0030] For the purposes of this invention, any given range includes both a lower limit and an upper limit. Unless otherwise stated, a given range (e.g., concentration, etc.) should be considered an approximation.

[0031] As described above, in a first aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for the prevention and / or treatment of diseases or disorders associated with uric acid monosodium hydrate crystallization, particularly gout.

[0032] Wherein, R1 and R2 are different and selected from -H and -(C1-C6)alkyl; R3 is selected from -H and =O; when R3 is -H... It is a double bond, when R3 is =0. It is a single key.

[0033] As used herein, the term "pharmaceutically acceptable salt" means a salt that, within reasonable medical judgment, is suitable for contact with tissues of humans and lower animals without causing excessive toxicity, irritation, allergic reactions, etc., and has a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. Examples of pharmaceutically acceptable, non-toxic acid addition salts include salts formed from amino groups with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with organic acids (such as acetic acid, trifluoroacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts prepared using other methods in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptyl sulfate, glycerol phosphate, gluconate, hemisulfate, heptaate, hexanoate, hydroiodate, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, and ammonium salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium salts. Where appropriate, other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions (such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate ions).

[0034] Those skilled in the art can prepare pharmaceutically acceptable salts of compounds of formula (I), particularly 7MX, using conventional methods.

[0035] As used herein, "disease or disorder associated with monosodium urate monohydrate crystallization" refers to any disease or disorder characterized by the presence of harmful monosodium urate monohydrate (MSU) crystals. The terms "monosodium urate monohydrate," "monosodium urate," "sodium urate," and "MSU" are used interchangeably in this application and refer to a compound with the molecular formula (NaC5H3N4O3·H2O) in which one uric acid molecule is bound to one sodium molecule and one water molecule. "Disease" refers to a state of health in which an animal is unable to maintain homeostasis, and if the disease is not treated, the animal's health condition will continue to deteriorate. In contrast, "disorder" refers to a state in which an animal is able to maintain homeostasis, but its health condition is worse than when it is not in a disorder. Without treatment, a disorder does not necessarily lead to further deterioration of the animal's health condition.

[0036] Unless otherwise stated, the term "treatment" as used herein refers to any type of therapy aimed at terminating, preventing, improving, or reducing susceptibility to a clinical condition or existing disease as described herein, including complete cure of the disease and improvement or relief of said disease. Therefore, "treatment," "treating," and their equivalents refer to achieving the desired pharmacological or physiological effect, encompassing any treatment of a subject's pathological condition or disorder. The terms "prevention" or "preventing" as used herein refer to, but are not limited to, preventative processes involving exposure of a subject to the compounds of the present invention prior to the induction or onset of a disease process.

[0037] The term "(C1-C6)alkyl" refers to a straight-chain or branched saturated hydrocarbon chain having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, n-pentyl, n-hexyl, etc., and more specifically, to a straight-chain or branched saturated hydrocarbon chain having 1 to 3 carbon atoms, and more specifically, methyl.

[0038] In one embodiment, the disease or disorder associated with the crystallization of sodium urate monohydrate is gout.

[0039] As used herein, the term "gout" refers to a systemic disease caused by the deposition of sodium urate crystals (MSU) in tissues, particularly joints. Joints may include, but are not limited to, the right or left metatarsophalangeal joint (MTP), ankle, dorsalis pedis joint, wrist, shoulder, hip, knee, elbow, metacarpophalangeal joint (MCP), interphalangeal joint (IP), proximal interphalangeal joint (PIP), or distal interphalangeal joint (DIP). Gout has multiple stages. For example, a patient or subject with "early gout" as described in this application refers to someone with hyperuricemia who has experienced only one or more gout attacks in their lifetime. A gout attack is an "attack" or exacerbation of gout symptoms and can occur at any time. A patient or subject with "late gout" as described in this application refers to someone with hyperuricemia who has experienced one or more (or more) gout attacks in their lifetime. The term "gout" as used in this application refers to both "early gout" and "late gout."

[0040] In one embodiment, R1 and R2 are different and selected from -H and -(C1-C3)alkyl. In a more specific embodiment, R1 and R2 are different and selected from -H and -CH3.

[0041] In one embodiment, R1 and R2 are different and selected from -H and -CH3, and R3 is -H. In another embodiment, R1 is -H, R2 is -CH3, and R3 is -H. In yet another embodiment, R1 is -CH3, R2 is -H, and R3 is -H.

[0042] In one embodiment, the compound is selected from the group consisting of 7-methylxanthine, 3-methylxanthine, 3-methyluric acid, 7-methyluric acid, and mixtures thereof. In a more specific embodiment, the compound is selected from the group consisting of 7-methylxanthine, 3-methylxanthine, 7-methyluric acid, and mixtures thereof. In a more specific embodiment, the compound is selected from 7-methylxanthine and 3-methylxanthine. In an even more specific embodiment, the compound is 7-methylxanthine.

[0043] The CAS number for 7-methylxanthine or 7MX (C6H6N4O2) is 552-62-5; the CAS number for 3-methylxanthine or 3MX (C6H6N4O2) is 1076-22-8; the CAS number for 7-methyluric acid or 7MU (C6H6N4O3) is 612-37-3; and the CAS number for 3-methyluric acid or 3MU (C6H6N4O3) is 605-99-2. All these compounds can be synthesized using conventional methods known in the art and are commercially available from various companies; for example, 7-methylxanthine is available from Sigma Aldrich (number 69723).

[0044] In one embodiment, the compound is used to prevent and / or treat diseases or disorders associated with the crystallization of sodium urate monohydrate, particularly gout. As used herein, the term "subject" refers to an animal, preferably a mammal, including humans or non-humans. The terms patient and subject are used interchangeably herein.

[0045] In one embodiment, the compound is used in a subject with hyperuricemia. As used herein, "hyperuricemia" refers to a subject with a serum urate or serum uric acid level greater than or equal to 7.0 mg / dL. Those skilled in the art will know how to measure serum urate or serum uric acid levels using conventional methods known in the art, such as the methods disclosed in the following examples.

[0046] In one embodiment, the compound of formula (I) is used to prevent and / or treat diseases or disorders associated with the crystallization of urate monosodium hydrate, particularly gout, by inhibiting the crystallization of urate monosodium hydrate and / or increasing the solubility of uric acid. In another embodiment, the compound of formula (I) is used to prevent and / or treat diseases or disorders associated with the crystallization of urate monosodium hydrate, particularly gout, by eliminating and / or preventing the formation of urate monosodium hydrate crystals.

[0047] In one embodiment, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 1 mg to 4000 mg, 10 mg to 3000 mg, 100 mg to 2000 mg, 500 mg to 1500 mg, or 800 mg to 1200 mg daily. More specifically, the dosage is 500 mg to 1500 mg daily.

[0048] In one embodiment, the compound is contained in a pharmaceutical composition, a nutritional health composition, a functional food, or a food supplement. In another embodiment, the compound is administered as a pharmaceutical composition, a nutritional health composition, a functional food, or a food supplement. In a more specific embodiment, the compound is contained in a pharmaceutical composition in a therapeutically effective amount together with one or more pharmaceutically acceptable excipients and / or carriers. In a more specific embodiment, the compound is administered as a pharmaceutical composition in a therapeutically effective amount together with one or more pharmaceutically acceptable excipients and / or carriers.

[0049] In this invention, "nutritional supplement composition" or "functional food" should be understood as a food that has beneficial effects on health. Similarly, the term nutritional supplement can be applied to extracts or chemical compounds obtained from common foods. Examples of foods with nutritional supplement properties include olive oil, red wine, broccoli, soybeans, etc. Nutritional supplements are commonly used in the nutritional blend and pharmaceutical industries. Just as some foods can be classified as nutritional supplements, certain nutritional supplements can be classified in the same way, such as fatty acids (e.g., omega-3 derived from fish oil and certain vegetables), or antioxidants and vitamins.

[0050] As used herein, the term "therapeuticly effective amount" refers to an amount of the compound or a pharmaceutically acceptable salt thereof that is sufficient, at the time of administration, to prevent or, to a certain extent, alleviate the development of one or more symptoms of the disease being treated. The specific dosage of the agent administered according to the invention will naturally depend on the specific circumstances, including the route of administration, the specific disease being treated, and similar considerations.

[0051] The phrase "pharmaceutically acceptable excipients and / or carriers" refers to pharmaceutically acceptable materials, compositions, or carriers. Each component must be pharmaceutically acceptable, meaning it is compatible with other components in the pharmaceutical composition. It must also be suitable for contact with human and non-human animal tissues or organs without excessive toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications, and have a reasonable benefit / risk ratio. Examples of suitable pharmaceutically acceptable excipients include solvents, dispersion media, diluents or other liquid carriers, dispersing or suspending agents, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, etc. Unless any conventional excipient medium is incompatible with a substance or its derivatives, for example, producing any adverse biological effects or interacting harmfully with any other component in the pharmaceutical composition, its use is within the scope of this invention.

[0052] The compounds and compositions provided by this invention can be administered via any suitable route, such as oral, parenteral, topical, intranasal, or sublingual, for which they will contain acceptable excipients required to formulate the desired dosage form. In one embodiment, the compounds or compositions are administered orally.

[0053] Those skilled in the art will recognize that the composition can be prepared using state-of-the-art excipients and conventional pharmaceutical techniques.

[0054] Compounds of formula (I), particularly 7MX, can be used in combination with one or more compounds that promote their absorption via a specific route of administration. Therefore, it can be administered with lactose, sucrose, talc, magnesium stearate, cellulose, calcium salts, gelatin, fatty acids, and other similar substances.

[0055] For therapeutic use, the compounds of formula (I), particularly 7MX, are in a pharmaceutically acceptable form or substantially pure, meaning they have a pharmaceutically acceptable purity other than conventional pharmaceutical additives (such as diluents and carriers) and do not contain any substances considered toxic at normal dose levels. The purity level of the active substance is particularly higher than 50%, more particularly higher than 70%, and even more particularly higher than 90%. In one specific embodiment, the level of the compound of formula (I) or a salt thereof is higher than 95%.

[0056] The dosage form may be a solid pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, such as tablets or coated tablets, powders, fine granules, granules, capsules (e.g., hard or soft gelatin capsules), lozenges, pills, and chewable preparations.

[0057] Alternatively, the pharmaceutical composition may be a semi-solid or liquid dosage form, such as a gel (e.g., hydrogel), cream, ointment, lotion, water-in-oil or oil-in-water emulsion, suspension, aerosol, and liquid formulation, such as solution, elixirs, and syrup (including dry syrup).

[0058] The preparation of the aforementioned drug dosage forms is well known in the prior art. The dosage can be appropriately controlled according to the desired drug formulation.

[0059] The pharmaceutical compositions of the present invention can be administered to patients in daily doses, once daily or in multiple divided doses. The amount of active ingredient can also be formulated into a single dose, provided it is reasonable from the perspective of pharmaceutical formulation.

[0060] In one embodiment, solid dosage forms (such as capsules, tablets, lozenges, granules, powders, or liquids) or other oral dosage forms may contain a compound of formula (I) or a pharmaceutically acceptable salt thereof, in amounts that allow each single dose to provide 1 mg to 4000 mg, 10 mg to 3000 mg, 100 mg to 2000 mg, 500 mg to 1500 mg, or 800 mg to 1200 mg of the active ingredient.

[0061] In preparing compositions containing compounds of formula (I), a variety of currently used additives may be used, such as fillers, thickeners, gelling agents, binders, disintegrants, surfactants, lubricants, coating agents, sustained-release agents, diluents, and / or one or more excipients. In addition to the additives described above, the formulations of the present invention may, if necessary, contain other additives, such as solubilizers, buffers, preservatives, isotonic agents, emulsifiers, suspending agents, dispersants, hardening agents, absorbents, binders, elasticizing agents, adsorbents, fragrances, colorants, flavoring agents, antioxidants, humectants, opacifiers, whitening agents, viscosity enhancers, oils, tableting aids, and / or antistatic agents.

[0062] More specifically, examples of such additives include one or more excipients, such as lactose, corn starch, mannitol, D-sorbitol, crystalline cellulose, erythritol, and sucrose; binders (such as hydroxypropyl cellulose (HPC-L), hydroxypropyl methylcellulose, polyvinylpyrrolidone, methylcellulose, and gelatinized starch); disintegrants (such as calcium carboxymethyl cellulose, sodium croscarmellose, and croscarmellose (crospovidone)); lubricants (such as magnesium stearate and talc); flavorings (such as flavorings or aromatic oils, such as apple flavoring, honey flavoring, 1-menthol, vanillin, lemon oil, cinnamon oil, mentha oil, or peppermint oil); and / or adsorbents (such as synthetic aluminum silicate and light anhydrous silicate).

[0063] In addition, coated pharmaceutical formulations can be prepared by using currently used coating agents such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, or polyvinylpyrrolidone.

[0064] Sweeteners may also be used, for example, in tablets, syrups, and chewable preparations, if desired. Specific examples of such sweeteners include mannitol, glucose, maltose, starch syrup, malt extract, maltitol, sorbitol, sucrose, unrefined sugar, fructose, lactose, honey, xylitol, hydrangea tea, saccharin, aspartame, cyclamate, Sunett®, aspartame, and other maltodextrin oligosaccharides, as well as oligosaccharides such as maltodextrin, reduced isomaltose, and raffinose, acesulfame potassium, or any kind of sugar alcohol or mixture thereof, such as sorbitol, mannitol, and / or xylitol.

[0065] As a solubilizer, any solubilizer known to be suitable for the pharmaceutical field can be used, such as polyethylene glycol, polyoxyethylene-polyoxypropylene copolymer (e.g., poloxamer 188), gycofurol, arginine, lysine, castor oil, propylene glycol, solketal, polysorbate, glycerin, polyvinylpyrrolidone, lecithin, cholesterol, 12-hydroxystearic acid-PEG660-ester, propylene glycol monostearate, polyoxy-40-hydrogenated castor oil, polyoxyethylene-10-oleyl-ether, polyoxy-20-cetearyl-stearyl ether, and polyoxy-40-stearate or mixtures thereof.

[0066] Any preservatives known for use in the pharmaceutical industry may be used, such as ethanol, benzoic acid and its sodium or potassium salts, sorbic acid and its sodium or potassium salts, chlorobutanol, benzyl alcohol, phenethyl alcohol, methylparaben, ethylparaben, propylparaben or butylparaben, phenol, m-cresol, p-chloro-m-cresol, those selected from PHB esters, such as mixtures of PHB-methyl ester and PHB-propyl ester, quaternary ammonium salts (such as benzalkonium chloride), thimerosal, phenylmercuric salts (such as nitrates, borates).

[0067] Buffer systems used to achieve the desired pH value can be, for example, glycine, a mixture of glycine and HCl, a mixture of glycine and sodium hydroxide solution and its sodium and potassium salts, a mixture of potassium hydrogen phthalate and hydrochloric acid, a mixture of potassium hydrogen phthalate and sodium hydroxide solution, or a mixture of glutamic acid and glutamate.

[0068] Suitable gelling agents are, for example, cellulose and its derivatives, such as methylcellulose, carboxymethylcellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, polyacrylate, poloxamer, tragacanth, carrageenan, starch and its derivatives, or any other gelling agent used in pharmaceutical technology.

[0069] Viscosity enhancers that may be mentioned include, for example, low amounts of the aforementioned gelling agents, glycerin, propylene glycol, polyethylene glycol, or polyols such as sorbitol and other sugar alcohols.

[0070] In addition to emulsifiers known in the prior art, the emulsifiers used may include polyoxyethylene derivatives of castor oil or polyoxyethylene alkyl ethers.

[0071] Suitable synthetic or natural colorants known in the pharmaceutical field can be used, such as indigo carmine.

[0072] Suitable oily components that may be present are any oily substances known in the art for the preparation of pharmaceuticals, such as vegetable oils (especially cottonseed oil, groundnut oil, peanut oil, corn oil, rapeseed oil, sesame oil, and soybean oil), or medium-chain triglycerides (e.g., fractionated coconut oil), or isopropyl myristate, isopropyl palmitate, or mineral oil or ethyl oleate.

[0073] The antioxidant used can be any antioxidant known in the prior art, such as α-tocopherol, butylated hydroxytoluene (BHT), or butylated hydroxyanisole (BHA).

[0074] Pharmaceutical compositions containing these additives can be prepared according to any method known in the art, depending on the dosage form. Of course, other additives not explicitly discussed may also be used in the formulations used according to the invention.

[0075] In one embodiment, the pharmaceutical composition is a compound of immediate-release (I) type (or a pharmaceutically acceptable salt thereof). These types of formulations allow for rapid release of the active ingredient to achieve rapid action on different tissues. In an alternative and further embodiment, the pharmaceutical composition is a composition that controls the release of the active ingredient over time, also known as a modified-release composition or dosage form. Specifically, it is designed to release the active ingredient over 1 to 2 days. More specifically, it is designed to release the active ingredient over 1 to 2 days and is formulated for administration to a subject once daily or every two days. These compositions allow for reduced dosing frequency and help simplify dosing regimens. Examples of these non-immediate-release formulations (where the active ingredient is released continuously over a period of time) include sustained-release compositions and extended-release compositions. Sustained-release dosage forms are designed to release (liberate) a drug at a predetermined rate to maintain a constant drug concentration and minimize side effects over a specific period of time. This can be achieved through a variety of formulations, including drug-polymer conjugates. Extended-release compositions refer to compositions that deliver a drug over a period of time (typically at a constant rate) or to a specific target in the body (targeted-release dosage forms).

[0076] In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered as a metabolic precursor.

[0077] As used herein, "metabolic precursor" refers to a compound that is metabolized by the subject's tissues or enzymes into a compound of formula (I), particularly 7MX, such as theobromine or caffeine (Arnaud MJ et al., "Pharmacokinetics and Metabolism of Natural Methylxanthines in Animal and Man", Methylxanthines. Handbook of Experimental Pharmacology, vol. 200). Therefore, in one embodiment, the metabolic precursor is theobromine or caffeine.

[0078] In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in the form of a composition comprising a metabolic precursor, particularly coffee or chocolate.

[0079] In one embodiment, the compound is administered in combination with a compound selected from the group consisting of colchicine, compounds that inhibit uric acid synthesis, compounds that promote uric acid excretion, nonsteroidal anti-inflammatory agents, corticosteroids, and mixtures thereof. In a more specific embodiment, the compound that inhibits uric acid synthesis is allopurinol or febuxostat, and / or, the compound that promotes uric acid excretion is selected from the group consisting of probenecid, sulfinpyrazone, benzbromarone, and recinard.

[0080] All the embodiments described above with respect to the first aspect are also applicable to the second and third aspects of the present invention.

[0081] In the specific embodiments of the second and third aspects, the compound is 7-methylxanthine.

[0082] In one specific embodiment of the second and third aspects, the disease or disorder associated with monosodium urate crystals is gout.

[0083] Throughout the specification and claims, the word "comprising" and its variations are not intended to exclude other technical features, additives, components, or steps. Furthermore, the word "comprising" covers situations where it "consists of...". Other objects, advantages, and features of the invention will be understood by those skilled in the art upon reading the specification, or may be learned by practicing the invention. The following embodiments and drawings are provided by way of illustration and are not intended to limit the invention. Moreover, the invention covers all possible combinations of the specific and preferred embodiments described herein.

[0084] For the sake of completeness, various aspects of the present invention are set forth in the following numbered clauses: Clause 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, for the prevention and / or treatment of diseases or disorders associated with crystallization of uric acid monosodium hydrate.

[0085] R1 and R2 are different and are selected from -H and -(C1-C6) alkyl groups; R3 is selected from -H and =O; and When R3 is -H It is a double bond, when R3 is =0. It is a single key.

[0086] Clause 2. The compound used according to Clause 1, wherein the disease or disorder associated with the crystallization of sodium urate monohydrate is gout.

[0087] Clause 3. A compound used in accordance with Clause 1 or 2, wherein R1 and R2 are different and selected from -H and -CH3.

[0088] Clause 4. A compound for use according to any one of Clauses 1-3, wherein the compound is selected from the group consisting of 7-methylxanthine, 3-methylxanthine and 7-methyluric acid; in particular, the compound is 7-methylxanthine.

[0089] Clause 5. A compound for any of the uses described in Clauses 1-4, wherein the compound is contained in a pharmaceutical composition, a nutritional health composition, a functional food, or a food supplement.

[0090] Clause 6. A compound for any of the uses described in Clauses 1-5, wherein the compound is administered in the form of a metabolic precursor.

[0091] Clause 7. A compound used in accordance with Clause 6, wherein the metabolic precursor is theobromine or caffeine.

[0092] Clause 8. A compound for any of the uses described in Clauses 1-7, wherein the compound is administered at a dose of 1 mg to 4000 mg daily.

[0093] Clause 9. The compound used according to Clause 8, wherein the compound is administered at a dose of 500 mg to 1500 mg daily.

[0094] Clause 10. A compound for any of the uses described in Clauses 1-9, wherein the compound is administered orally.

[0095] Clause 11. A compound for any of the uses described in Clauses 1-10, wherein the compound is administered in combination with a compound selected from colchicine, a compound that inhibits uric acid synthesis, a compound that promotes uric acid excretion, a nonsteroidal anti-inflammatory agent, a corticosteroid, or a mixture thereof.

[0096] Clause 12. A compound used according to Clause 11, wherein the compound that inhibits uric acid synthesis is allopurinol or febuxostat.

[0097] Clause 13. A compound for use as described in Clause 11 or 12, wherein the compound that promotes uric acid excretion is selected from the group consisting of probenecid, sulfinpyrazone, benzbromarone, and resinard.

[0098] Clause 14. An in vitro method for eliminating and / or preventing the formation of urate monosodium hydrate crystals in a composition containing uric acid, said method comprising contacting said composition with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0099] Wherein, R1 and R2 are different and selected from -H and -(C1-C6)alkyl; R3 is selected from -H and =O; and when R3 is -H... It is a double bond, when R3 is =0. It is a single key.

[0100] Clause 15. In vitro use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the elimination and / or prevention of the formation of uric acid monosodium hydrate crystals.

[0101] Wherein, R1 and R2 are different and selected from -H and -(C1-C6)alkyl; R3 is selected from -H and =O; when R3 is -H... It is a double bond, when R3 is =0. It is a single key.

[0102] Example The effects of different methylxanthines on the crystallization of uric acid monosodium hydrate (MSU) were investigated in an in vitro model. Specifically, the ability of the following substances to inhibit MSU crystallization was evaluated: -Caffeine (1,3,7-trimethylxanthine) (CF) -Theobromine (3,7-dimethylxanthine) (TB) -Theophylline (1,3-dimethylxanthine) (TF) 1-Methylxanthine (1MX) 3-Methylxanthine (3MX) 7-Methylxanthine (7MX) -Dihydroxypropyltheophylline (DF) -Ethyltheophylline (EF) -Pentoxyfilline (PF) 1,3-Dimethyluric acid (1,3DMU) 7-Methyluric acid (7MU) Each 0.3 mM methylxanthine was added to a well containing 375 mg / L (2.23 mM) uric acid, 400 mM sodium ions, and 12 mM phosphate buffer at pH 7.4. The plate was incubated for 6 days (144 hours), and then the formation of MSU crystals was analyzed.

[0103] The formation of MSU crystals was assessed by visual observation and by determining the concentration of residual uric acid in the solution using a modified phosphotungstic acid method. In short, the modified phosphotungstic acid method involves mixing each well-diluted sample with a solution of phosphotungstic acid and sodium carbonate, followed by incubation at 25°C for 25 minutes. The optical density of the tungsten blue product was read at 700 nm using a 96-well plate reader and compared with a calibration curve.

[0104] like Figure 1 and 2 As shown, most of the methylxanthines tested had no significant effect on the crystallization of MSU. However, 7-methylxanthine, 3-methylxanthine, and 7-methyluric acid unexpectedly exhibited a strong inhibitory effect on the formation of these crystals. This effect was not only significant in inhibiting crystallization but also significantly increased the solubility of sodium urate in the test fluid. Without being bound by any theory, this increase in solubility may be attributed to the formation of stable “clusters” of urate ions with 7-methylxanthine, 3-methylxanthine, or 7-methyluric acid in the liquid medium, thereby reducing the actual supersaturation of sodium urate in the blood. Therefore, this is likely primarily a thermodynamic effect rather than a kinetic one.

[0105] Subsequently, the effect of 7-methylxanthine on MSU crystal formation was tested at different concentrations (50 µM, 100 µM, and 150 µM), repeated three times. Figure 3 As shown, at all tested concentrations, 7-methylxanthine completely inhibited the formation of MSU crystals after 3 days.

[0106] Next, the inhibitory effects of different concentrations of 7-methylxanthine and 3-methylxanthine were compared after 5 days. Figure 4 As shown, both 7-methylxanthine and 3-methylxanthine were able to inhibit the formation of MSU crystals at concentrations as low as 50 μM, which was confirmed by the increase in uric acid in the solution. However, 7-methylxanthine showed a significantly stronger inhibitory effect on crystallization compared to 3-methylxanthine.

[0107] Then, the effect of the combination of 7-methylxanthine and 3-methylxanthine on MSU crystallization was tested. Figure 5As shown, the combination of 7-methylxanthine and 3-methylxanthine further inhibited the formation of MSU crystals.

[0108] The minimum concentration of 7-methylxanthine required to completely inhibit MSU crystallization at different uric acid concentrations was also investigated. The test conditions are shown in Table 1. Table 1

[0109] Figure 6 , 7 Figures 9 and 1 show the concentrations of uric acid in the solution after 3, 4, and 5 days, respectively. Figure 8 The image shows a plate after 5 days of incubation.

[0110] according to Figure 8 and 9 The data shown determined the minimum concentration of 7-methylxanthine that completely prevents the formation of sodium urate crystals (C100), such as Figure 10 And as shown in Table 2: Table 2

[0111] These results indicate that even at higher concentrations of sodium urate than in the interstitial fluid, low concentrations of 7-methylxanthine can prevent sodium urate crystallization. Specifically, the results presented here show how a concentration of approximately 6 mg / L of 7-methylxanthine can inhibit sodium urate crystal formation for over 48 hours, demonstrating the significant role of 7-methylxanthine in the prevention of gout. 3-methylxanthine also exhibited significant inhibitory activity, although at the same concentration, its effect was approximately half that observed with 7-methylxanthine. The effect of 7-methyluric acid is similar to that of 7-methylxanthine.

[0112] Although the results showed that caffeine did not affect the crystallization process of sodium urate, it is known that when caffeine is taken orally, 8% is metabolized to 7-methylxanthine, and when theobromine (dark chocolate) is taken orally, 30% is metabolized to 7-methylxanthine. Therefore, these results suggest that 7-methylxanthine can be administered directly to subjects, or indirectly in the form of caffeine or theobromine, to treat or prevent gout.

[0113] It should also be noted that 7-methylxanthine's increased solubility of sodium urate may promote its redissolution process, thus it is also important in the treatment of gout attacks.

[0114] One important aspect to consider is that 7-methylxanthine has been used to treat myopia, and its toxicity has been studied, concluding that doses up to 400 mg three times daily do not produce any toxicity. Therefore, 7-methylxanthine is not only an effective drug for treating gout, but also a safe and reliable treatment.

[0115] Finally, it can be considered that since there are no side effects associated with the administration of 7-methylxanthine, it can also be administered in combination with drugs that block uric acid production (such as allopurinol or febuxostat). In this case, the dosage of these drugs can be reduced, thus minimizing or avoiding their side effects.

[0116] Citation List Arnaud MJ et al., "Pharmacokinetics and Metabolism of Natural Methylxanthines in Animal and Man", Methylxanthines. Handbook of ExperimentalPharmacology, vol. 200.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, for the prevention and / or treatment of gout, in, R1 and R2 are different and are selected from -H and -(C1-C6) alkyl groups; R3 is selected from -H and =O; and When R3 is -H It is a double bond, when R3 is =0. It is a single key.

2. The compound for the use according to claim 1, wherein, R1 and R2 are different and are selected from -H and -CH3.

3. The compound for the use according to claim 1 or 2, wherein, The compound is selected from the group consisting of 7-methylxanthine, 3-methylxanthine and 7-methyluric acid; specifically, the compound is 7-methylxanthine.

4. The compound for use according to any one of claims 1-3, wherein the compound is contained in a pharmaceutical composition, a nutritional health composition, a functional food, or a food supplement.

5. The compound for use according to any one of claims 1-4, wherein the compound is administered in the form of a metabolic precursor.

6. The compound for the use according to claim 5, wherein, The metabolic precursor is theobromine or caffeine.

7. The compound for use according to any one of claims 1-6, wherein, The subjects had hyperuricemia.

8. The compound for use according to any one of claims 1-7, wherein the compound is administered at a dose of 1 mg to 4000 mg daily.

9. The compound for use according to claim 8, wherein the compound is administered at a dose of 500 mg to 1500 mg daily.

10. The compound for use according to any one of claims 1-9, wherein the compound is administered orally.

11. The compound for use according to any one of claims 1-10, wherein the compound is administered in combination with a compound selected from the group consisting of colchicine, compounds that inhibit uric acid synthesis, compounds that promote uric acid excretion, nonsteroidal anti-inflammatory agents, corticosteroids, and mixtures thereof.

12. The compound for the use according to claim 11, wherein, The compound that inhibits uric acid synthesis is allopurinol or febuxostat.

13. The compound for the use according to claim 11 or 12, wherein, The compounds that promote uric acid excretion are selected from the group consisting of probenecid, sulfinpyrazone, benzbromarone, and resinard.

14. An in vitro method for eliminating and / or preventing the formation of urate monosodium hydrate crystals in a composition containing uric acid, the method comprising contacting the composition with a compound of formula (I) or a pharmaceutically acceptable salt thereof, in, R1 and R2 are different and selected from -H and -(C1-C6) alkyl groups; R3 is selected from -H and =O; when R3 is -H... It is a double bond, when R3 is =0. It is a single key.

15. The in vitro use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the elimination and / or prevention of the formation of uric acid monosodium hydrate crystals, in, R1 and R2 are different and selected from -H and -(C1-C6) alkyl groups; R3 is selected from -H and =O; when R3 is -H... It is a double bond, when R3 is =0. It is a single key.

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