• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    Xanthine crystallization inhibitors. The present invention refers to a compound of the formula (1), a pharmaceutically acceptable salt or solvate thereof, wherein R1 is H or an alkyl group (C1 -C3), R2 is H or an alkyl group (C1 -C3), R3 is H or an alkyl group (C1 -C3), with the proviso that at least one of R1, R2 or R3 is an alkyl group (C1 -C3, for use in the treatment and/or prevention of xanthine urolithiasis. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2728434A1
    申请号:ES201830385
    申请日:2018-04-20
    公开日:2019-10-24
    发明作者:Bauzá Antonia Costa；Freixedas Felix Grases；Rodríguez Adrián Rodríguez
    申请人:Universitat de les Illes Balears；
    IPC主号:
    专利说明:

    [0001]
    [0002] Xanthine Crystallization Inhibitors
    [0003]
    [0004] The present invention refers to inhibitors of xanthine crystallization for use in the treatment and / or prevention of xanthine urolithiasis.
    [0005]
    [0006]
    [0007]
    [0008] Xanthine urolithiasis is a rare type of kidney stones and is a consequence of a rare inherited disorder (xanthuria). Xanthuria is a consequence of a deficiency of xanthine oxidase activity in tissues, resulting in hypouricemia and hypouricosuria (Carpenter TO, et al. Hereditary xanthinuria presenting in infancy nephrolithiasis. J Pediatr 1986; 109: 309-9; Mateos FA , et al., Hereditary xanthinuria: Evidence for enhanced hypoxanthine salvage. J Clin Invest 1987; 79: 847-52). The appearance of symptoms can occur at any age. Approximately 50% of patients have symptoms of urinary tract infection, hematuria, renal colic, acute renal failure and urolithiasis. In some exceptional patients, kidney disease can progress to renal failure, or it can even cause arthropathy, myopathy or duodenal ulcer.
    [0009]
    [0010] In fact, hereditary xanthuria is a consequence of the mutation of the xanthine dehydrogenase (XDH, 2p23.1) or cofactor molybdenum sulforase (MOCOS, 18q12.2) genes, which causes a breakdown in the degradation of hypoxanthine and xanthine to uric acid and that leads to the accumulation of xanthine and, to a lesser extent, hypoxanthine. Classic hereditary xanthuria includes xanthuria type I and II. Type I corresponds to a deficit of xanthine dehydrogenase / oxidase, by mutation of XDH, while type II is the result of the combination of xanthine dehydrogenase and aldehyde oxidase by mutations of MOCOS. Both enzyme deficiencies lead to a clinically identical phenotype.
    [0011]
    [0012] The diagnosis of this disorder is based on measurements of uric acid in plasma and urine. If abnormally low values are detected, the measurement of Xanthine and hypoxanthine levels in urine and plasma. In approximately half of these patients the presence of xanthine urolithiasis is detected. In a few cases the disease can end in renal failure.
    [0013]
    [0014] The only recommended treatment for these patients is a low purine diet and a high fluid intake. Because the solubility of xanthine does not depend on the pH values of the urine, the alkalinization of the urine has no effect, contrary to what occurs in the case of uric lithiasis (Nicoletta JA, et al., Medical evaluation and treatment of urolithiasis Pediatr Clin North Am 2006; 53: 479-91; Hisatome I, et al., Renal hypouricemia due to enhanced tubular secretion of urate associated with urolithiasis: successful treatment of urolithiasis by alkalinization of urine K +, Na + - citrate Nephron 1993; 65: 578-82).
    [0015]
    [0016] Therefore, there is a need to identify new agents that can be used clinically to prevent the development of xanthine crystals in the urine, avoiding the development of the corresponding stones, a very important problem in patients with xanthuria.
    [0017]
    [0018]
    [0019]
    [0020] The object of the present invention is to provide new products for the treatment and / or prevention of xanthine urolithiasis based on the discovery of new inhibitors of xanthine crystallization.
    [0021]
    [0022] Therefore, a main aspect of the present invention refers to a compound of the general formula (I):
    [0023]
    [0024]
    [0025] a pharmaceutically acceptable salt or solvate thereof, wherein
    [0026] R1 is H or a (C1-C3) alkyl group,
    [0027] R2 is H or a (C1-C3) alkyl group,
    [0028] R3 is H or a (C1-C3) alkyl group,
    [0029] with the proviso that at least one of R1, R2 or R3 is a (C1-C3) alkyl group, for use in the treatment and / or prevention of xanthine urolithiasis.
    [0030]
    [0031] The term "(C1-C3) alkyl group" in the present invention refers to a saturated linear or branched hydrocarbon chain having 1 to 3 carbon atoms, for example, methyl, ethyl, n-propyl, / -propyl , more particularly it is a methyl.
    [0032]
    [0033] The term "urolithiasis" refers to the disorder caused by the presence of stones or stones inside the kidneys or urinary tract (ureters, vegija). "Urolithiasis", "nephrolithiasis" and "renal lithiasis" are synonyms. In the case of xanthine urolithiasis, kidney stones are composed of xanthine that has concentrated and precipitated forming fragments of varying size.
    [0034]
    [0035] Pharmaceutically acceptable salts include, for example, acetate, gluconate, oleate or salicylate.
    [0036]
    [0037] As shown in the Examples below, the compounds encompassed by formula (I) are effective as inhibitors of xanthine crystallization, thus being useful in the prevention and treatment of xanthine urolithiasis. Xanthine crystallization inhibitors of the invention prevent the development of stones or reduce the size of stones that have already formed, allowing their excretion in the urine. Xanthine crystallization inhibitors are also useful in preventing recurrence of urolithiasis episodes. In addition, the compounds of the invention are useful in improving the symptoms associated with xanthuria disease.
    [0038]
    [0039] Experimental results show that the compounds 1-methylxanthine (1-MX), 7-methylxanthine (7-MX) and 3-methylxanthine (3-MX) can inhibit the nucleation of xanthine, since the delay in induction time in Crystal development depends on the concentrations of 1-MX, 7-MX and 3-MX. Curiously, the inventors have observed that the compounds very similar in structure to formula (I) such as hypoxanthine (HX), theophylline (TP), paraxanthine (PX), theobromine (TB), caffeine (CF), 1-methyluric acid (1 -MU) and 1,3-dimethyluric acid (1,3-DMUA) showed no inhibitory effect. It is interesting to observe the selectivity of the crystallization inhibition process. Therefore, only methyl xanthines in position 1, 7 and 3 can be incorporated into the crystalline network of xanthine. The incorporation of these molecules into the crystalline network of xanthine would modify the structure of some layers that, as a consequence, increase their energy, modifying their growth rate. In this case, because the urine pH does not affect the solubility of xanthine, inhibition studies have been carried out at a single pH value (pH = 6). Interestingly, neither the CF, nor the PX or TP showed inhibitory effects, which demonstrates the importance of the positions of the methyl groups in the inhibitory effects shown by the molecule.
    [0040]
    [0041] A further aspect of the present invention refers to a composition comprising the compound of formula (I) as described above for the treatment and / or prevention of xanthine urolithiasis.
    [0042]
    [0043] As discussed, a first aspect of the invention refers to the compounds of the formula (I).
    [0044]
    [0045] In a particular embodiment, R1 is a (C1-C3) alkyl group, R2 is a (C1-C3) alkyl group and R3 is H.
    [0046]
    [0047] In a particular embodiment, R1 is a (C1-C3) alkyl group, R2 is H and R3 is H.
    [0048]
    [0049] In a particular embodiment, R1 is H and R2 is a (C1-C3) alkyl group and R3 is H.
    [0050]
    [0051] In a particular embodiment, R1 is H, R2 is H and R3 is a (C1-C3) alkyl group.
    [0052]
    [0053] In a particular embodiment, R1 is a methyl.
    [0054]
    [0055] In another particular embodiment, R2 is a methyl.
    [0056]
    [0057] In another particular embodiment, R3 is a methyl.
    [0058] In a particular embodiment, the compound of the formula (I) is selected from the group consisting of theobromine, 1-methylxanthine (1-MX), 3-methylxanthine (3-MX) and 7-methylxanthine (7-MX).
    [0059]
    [0060] In a more particular embodiment, the compound of the formula (I) is theobromine:
    [0061]
    [0062]
    [0063]
    [0064]
    [0065] In another more particular embodiment, the compound of the formula (I) is 3-methylxanthine:
    [0066]
    [0067]
    [0068]
    [0069]
    [0070] In another more particular embodiment, the compound of the formula (I) is 7-methylxanthine:
    [0071]
    [0072]
    [0073] In another more particular embodiment, the compound of the formula (I) is 1-methylxanthine:
    [0074]
    [0075]
    [0076]
    [0077]
    [0078] In a particular embodiment, the compound of the formula (I) is administered orally.
    [0079]
    [0080] In a particular embodiment, the dose administered, particularly orally, of the compound of formula (I) varies between 100 mg / day and 400 mg / day, more particularly 200 mg / day.
    [0081]
    [0082] The compound with the formula (I) can be administered in solid form (including granules, powders or suppositories) or in liquid form (such as solutions, suspensions or emulsions). It can be administered in this way or even after being subjected to operations such as sterilization or the addition of preservatives, stabilizers or emulsifiers.
    [0083]
    [0084] The compounds of the formula (I) may be in pure form or be comprised of natural products. Theobromine for example is present in high amounts in cocoa and chocolate (Craig WJ, et al., Caffeine and theobromine levels in cocoa and carob products 2006; J Food Sci, 49: 302-303). Cocoa powder can vary in quantity and theobromine, from 2% theobromine, to higher levels of about 10%. There are usually higher concentrations in dark chocolate than in milk chocolate. A piece of dark or bitter chocolate, which contains a minimum of 34% to a maximum of 98% cocoa, may contain an average of 378 mg theobromine. Theobromine can also be found in small amounts in cola nut (1.0-2.5%), guarana berry, yerba mate ( Ilex paraguariensis), and the tea plant. Cocoa beans contain Natural form about 1% theobromine. The plant species with the highest amounts of theobromine are: Theobroma cacao, Theobroma bicolor, Ilex paraguariensis, Ilex guayusa, Camellia sinensis, Cola acuminata, Theobroma angustifolium, Guarana, Coffea Arabica.
    [0085]
    [0086] In a particular embodiment, the compound of the formula (I) is theobromine and is comprised in cocoa or chocolate.
    [0087]
    [0088] In a more particular embodiment, a cocoa powder extract with 40% flavonols (theobromine) is used.
    [0089]
    [0090] It is important to consider that 7-MX and 3-MX are two important metabolites of theobromine. Therefore, after consumption of theobromine, 20% is excreted as TB, 21.5% is excreted as 3-MX and 36% is excreted as 7-MX. 1-MX is not a metabolite of theobromine, it is only a product that is obtained as a result of 19% caffeine metabolism (Maurice J. Arnaud, Pharmacokinetics and metabolism of natural methylxanthines in animal and man, in: Bertid B Fredholm (Ed), Methylxanthines, Springer, 2011, New York, pp. 33-91).
    [0091]
    [0092] It can be considered that, for example, the daily intake of only 200 mg of TB would lead to the excretion of 43 mg of 3-MX and 72 mg of 7-MX. These amounts, according to the results presented here, could cause a significant inhibition of the development of xanthine crystals in the urine and therefore could protect patients with xanthuria from developing kidney stones generated by this substance.
    [0093]
    [0094] The compounds of the formula (I) can also be obtained by chemical synthesis.
    [0095]
    [0096] The invention further refers to a composition comprising the compounds defined above, for use in the treatment and / or prevention of xanthine urolithiasis.
    [0097]
    [0098] The composition could be a pharmaceutical composition or a supplement food
    [0099]
    [0100] In a particular embodiment, the composition is a pharmaceutical composition, wherein the compound of the formula (I) is combined with pharmaceutically acceptable excipients.
    [0101]
    [0102] Depending on the pharmaceutical composition of interest, the skilled person knows numerous possible suitable pharmaceutically acceptable excipients. For example, if the composition is a suspension a suitable pharmaceutically acceptable excipient could for example be polysorbate (for example, polysorbate 20 = Tween 20), which could be a suitable excipient present in a suitable percentage in, for example, an aqueous medium. If the pharmaceutical composition is a tablet, suitable pharmaceutically acceptable excipients could be, for example, diluents, binders (eg, methyl cellulose), lubricants, etc. An antioxidant agent such as, for example, ascorbic acid is also an example of a pharmaceutically acceptable excipient. In addition, in some cases water can also be considered a pharmaceutically acceptable excipient.
    [0103]
    [0104] In the pharmaceutical composition, the compound with formula (I) can be combined with one or more compounds that facilitate its absorption through a selected route of administration. It can, therefore, be administered with lactose, sucrose, talc, magnesium stearate, cellulose, calcium salts, gelatin, fatty acids, in addition to other similar substances.
    [0105]
    [0106] In particular, the pharmaceutical composition is administered orally.
    [0107]
    [0108] Pharmaceutically acceptable adjuvants and vehicles that can be used in the compositions are adjuvants and vehicles known to those skilled in the art and are commonly used in the preparation of therapeutic compositions.
    [0109]
    [0110] The term "food supplement" composition is used in the present patent to define an ingestible food product (which can be consumed or drunk).
    [0111] For therapeutic use, it is preferable if the compound with the formula (I) is in a pharmaceutically acceptable form or is substantially pure, that is, having a pharmaceutically acceptable level of purity excluding usual pharmaceutical additives, such as diluents and transporters, and is free of any material that is considered toxic at usual dosage levels. The purity levels for the active substance are particularly above 50%, more particularly above 70%, and even more particularly above 90%. In a particular embodiment, the levels of the compound with the formula (I), or its salts or solvates, are above 95%.
    [0112]
    [0113] As stated above, the invention refers to the compounds of the formula (I) or compositions for the treatment and / or prevention of xanthine urolithiasis. Alternatively, the invention refers to a method for treating and / or avoiding xanthine urolithiasis which comprises administering a compound or a composition of the invention to a subject in need thereof. Alternatively, the invention refers to the use of a compound or composition of the invention for the preparation of a medicament for the prevention and / or treatment of xanthine urolithiasis.
    [0114]
    [0115] It is widely understood that the term "Treatment" which refers to reducing the potential for a certain disease, reducing the presence of a certain disease, and / or a reduction in the severity of a particular disease, to a degree to which the subject does not suffer more discomfort and / or altered function due to it. "Treatment" refers to a desired therapeutic benefit or clinical outcome, which is not necessarily a cure for a particular disease or disorder, but encompasses a result that usually includes disease relief, disease elimination, reduction or relief of a symptom associated with the disease, prevention of a secondary disease that is the result of the presence of a primary disease, decrease in the degree of the disease, stabilized state (i.e., without worsening) of the disease, delay or slowing of disease progression, improvement or attenuation of disease status, and remission (either partial or total), whether detectable or undetectable of the disease.
    [0116] "Prevention" aims to prevent the occurrence of such disease. Prevention can be complete (for example, the total absence of a disease). Prevention can also be partial, such that for example the presence of a disease in a subject is less than what would have happened without the administration of the compounds of the present invention. Prevention also refers to reduced susceptibility to a clinical condition.
    [0117]
    [0118] Unless defined otherwise, all technical and scientific terms used in this patent have the same meaning as that which is commonly understood by a person skilled in the art to which this invention belongs. Methods and materials similar or equivalent to those described in the present patent can be used in the practice of the present invention. Throughout the description and the claims the word "comprises" and its variations are not intended to exclude other technical characteristics, additives, components, or steps. Additional objects, advantages and features of the invention will be apparent to those skilled in the art when examining the description or can be learned through the practice of the invention. In addition, the present invention covers all possible combinations of the particular embodiments described in the present patent. The following examples, drawings are provided by way of illustration and are not intended to be limiting of the present invention.
    [0119]
    [0120] BRIEF DESCRIPTION OF THE DRAWINGS
    [0121]
    [0122] FIG. 1 : Crystallization curves for 500 mg / L xanthine in synthetic urine, in the absence of inhibitors, and in the presence of 20 mg / l of 1-MX, 20 mg / l of 3-MX and 20 mg / l of 7-MX (T = 37 oC; pH = 6.0). The absorbance (at 550 nm) is represented by time (in minutes).
    [0123]
    [0124] FIG. 2: Scanning electron microscope images of xanthine crystals obtained in synthetic urine containing 400 mg / L of xanthine, and incubated 24 h at 37 ° C, in the presence of different inhibitors as follows: (A) without inhibitors; (B) with 20 mg / L of 3-MX; (C) with 40 mg / L of 3-MX; (D) with 20 mg / L 7-MX; (E) with 40 mg / L of 7-MX; (F) with 20 mg / L of 3-MX and 20 mg / L of 7-MX and (G) and (H) with 20 mg / L of 3-MX and 40 mg / L of 7-MX.
    [0125]
    [0126]
    [0127]
    [0128] Example 1: Study of inhibition of crystallization of xanthine by 3-methylxanthine (3-MX) and 7-methylxanthine (7-MX)
    [0129]
    [0130] Materials and methods
    [0131]
    [0132] Reagents and solutions
    [0133] Xanthine (X), 1-methylxanthine (1-MX), 3-methylxanthine (3-MX) and 7-methylxanthine (7-MX) were purchased from Sigma-Aldrich (St Louis, MO, USA). Synthetic urine components were obtained from Panreac (Montcada i Reixac, Barcelona, Spain). Analytical reagent grade purity chemicals were dissolved in ultra-pure deionized water of a Milli-Q system and filtered through 0.45 µm pore filters before use. A stock solution of xanthine was prepared daily by dissolving 0.5 g of xanthine in 0.1 L of a 1 M NaOH solution. To prevent precipitation of other compounds such as calcium oxalate, calcium phosphate, or ammonium phosphate and magnesium, crystallizations were performed in simplified synthetic urine, prepared by dissolving 5.60 g of Na2HPO412H2O; 2.41 g NaH2PO4-2H2O and 13.05 g NaCl in 1L of H2O.
    [0134]
    [0135] Turbidimetric test
    [0136] The formation of xanthine crystals in synthetic urine and the effects of 1-methylxanthine (1-MX), 3-methylxanthine (3-MX) and 7-methylxanthine (7-MX) were evaluated using a kinetic turbodimetric system, consisting of a photometer (Metrohm 662) equipped with a fiber optic light guide detector cell with a 2x10 mm optical path coupled reflector and monochromatic light (550 nm). Crystallization was evaluated at constant temperature (37oC) with magnetic stirring.
    [0137]
    [0138] Synthetic urine (180 mL) was added to a crystallization flask, followed by a solution of 20 mL of xanthine. The final concentration of xanthine was 500 mg / L. Yes an inhibitor was tested, it was dissolved in the corresponding amount in this solution. When the resulting solution reached a temperature of 37 ° C, 3.6 mL of 6 M HCl was added to achieve a pH of 6.0, which is the normal urine pH, and the timer was started. The pH of the final solution was measured at the beginning of each experiment. The absorbance of the solution (550 nm) was recorded during the entire kinetic test.
    [0139]
    [0140] The maximum concentrations tested were: 20 mg / L for 1-MX, 20 mg / L for 3-MX; 40 mg / L for 7-MX. The minimum amounts tested for the three methylxanthines (1-MX, 3-MX and 7-MX) from which crystallization inhibitory effects have already been observed correspond to 5mg / L.
    [0141]
    [0142] Crystal development analysis
    [0143] 100 mL of synthetic urine aliquot containing 400 mg / L of xanthine was added at pH = 6.0 to 7 crystallization plates: one without inhibitors, two with 20 and 40 mg / L of 3-MX; two with 20 and 40 mg / L of 7-MX; one with a mixture of 20 mg / L of 3-MX and 20 mg / L of 7-MX; and the last one with a mixture of 20 mg / L of 3-MX and 40 mg / L of 7-MX. The plates were covered with parafilm plastic film and incubated without shaking at 37 ° C for 24 h. The crystals formed were carefully collected, dried, and examined under a scanning electron microscope.
    [0144]
    [0145] Results
    [0146]
    [0147] The compounds 7-MX and 3-MX in addition to different mixtures of 1-MX, 3-MX and 7-MX (5, 10 and 20 mg of each substance, showed remarkable inhibitory effects on the crystallization of xanthine, as You can see in FIG. 1.
    [0148]
    [0149] Scanning electron microscope images of crystals formed in the presence of 7-MX, 3-MX and mixtures of 3-MX and 7-MX are shown in FIG. 2. (A) without inhibitors, (B) 20 mg / L of 3-MX, (C) 40 mg / L of 3-MX, (D) 20 mg / L of 7-MX, (E) 40 mg / L of 7-MX, (F) 20 mg / L of 3-MX 20 mg / L of 7-MX, (G), 20 mg / L of 3-MX 40 mg / L of 7-MX (H). As can be seen in the presence of the inhibitors, because the induction time of the crystallization was longer, the nucleation of the crystalline phase was less abundant and the crystals formed more slowly. As a consequence, leading to more crystalline material and also to larger crystals, with well developed faces, which clearly demonstrates the effects of these crystallization inhibitors. The inhibitors are specifically adsorbed only on certain faces, since the adsorption process depends on the molecular structure of the inhibitor and the structure of the face (which determines the establishment of stable interactions). As a consequence of adsorption on specific faces, the growth rate thereof is modified and this leads to modifications in the morphology of the crystals, as shown in FIG 2. On the other hand, the greater the inhibitory effect, fewer nuclei are formed and as a consequence, in very long times (experiment of FIG.
    [0150] 2), the crystals formed are much larger since the supersaturated material will be distributed between a few cores (FIG. 2, G, H).
    [0151]
    [0152] Example 2: (Comparative example) Study of the inhibition of crystallization of xanthine by hypoxanthine (HX), theophylline (TP), paraxanthine (PX), theobromine (TB), caffeine (CF), 1-methyluric acid (1- MU) and 1,3-dimethyluric acid (1,3-DMUA):
    [0153]
    [0154] The compounds tested in this example have similar structures to that of the compound (I) of the present invention, but are outside the scope of the present invention.
    [0155]
    [0156] Hypoxanthine (HX), theophylline (TP), paraxanthine (PX), theobromine (TB), caffeine (CF), 1-methyluric acid (1-MU) and 1,3-dimethyluric acid (1,3-DMUA) were acquired from Sigma-Aldrich (St Louis, MO, USA).
    [0157]
    [0158] The same procedure described in example 1 to study the inhibition of xanthine crystallization was carried out in this example for the compounds mentioned (X, HX, TP, PX, TB, CF, 1-MU and 1,3- DMUA).
    [0159]
    [0160] The maximum concentration tested for all compounds was: 40 mg / L for TB, TP, PX and CF; 45 mg / L for 1-MU; 80 mg / L for 1,3-DMU and 200 mg / L for HX.
    [0161] Results
    [0162]
    [0163] TB, TP, PX, CF, MU, 1,3-DMU and HX did not cause effects at the highest concentration studied. It is interesting to observe the specificity of the crystallization inhibitors in the case of molecular crystals, as in this case, which is a consequence, as already mentioned, of the interaction between the inhibitor and the corresponding crystalline face, which is selectively determined by the structure of both entities, similar to the interaction between enzyme-substrate.
    [0164]
    [0165] Conclusions
    [0166]
    [0167] From the present results, it is shown that 1-MX, 7-MX and 3-MX show significant inhibitory effects of xanthine crystallization. Substances can inhibit xanthine nucleation, since the delay in induction time depends on the concentrations of 1-MX, 7-MX and 3-MX. It is interesting to observe how HX, TP, PX, TB, CF, 1-MU and 1,3-DMU showed no inhibitory effect. It is interesting to observe the selectivity of the crystallization inhibition process. Therefore, only methyl xanthines in position 1, 7 and 3 are capable of being incorporated into the crystalline network of xanthine. The incorporation of these molecules into the crystalline network of xanthine would modify the structure of some layers that, as a consequence, increase their energy, alternating their growth rate. In this case, because the urine pH does not affect the solubility of xanthine, inhibition studies have been performed at a single pH value (pH = 6). Interestingly, neither CF nor PX nor TP showed inhibitory effects, which demonstrates the importance of the positions of methyl groups in the inhibitory effects shown by the molecule.
    权利要求:
    Claims (15)
    [1]
    1.- A compound of the formula (I),

    [2]
    2. - Compound for use according to claim 1, wherein R1 is a (C1-C3) alkyl group, R2 is (C1-C3) alkyl group and R3 is H.
    [3]
    3. - Compound for use according to claim 1, wherein R1 is a (C1-C3) alkyl group, R2 is H and R3 is H.
    [4]
    4. - Compound for use according to claim 1, wherein R1 is H and R2 is a (C1-C3) alkyl group and R3 is H.
    [5]
    5. - Compound for use according to claim 1, wherein R1 is H, R2 is H and R3 is a (C1-C3) alkyl group.
    [6]
    6. - Compound for use according to any of claims 1-3, wherein R1 is methyl.
    [7]
    7. - Compound for use according to any of claims 1, 2 or 4, wherein R2 is methyl.
    [8]
    8. - Compound for use according to any of claims 1 or 5, wherein R3 is methyl.
    [9]
    9. - Compound for use according to claim 1, wherein the compound of the formula (I) is selected from the group consisting of theobromine, 1-methylxanthine, 3-methylxanthine and 7-methylxanthine.
    [10]
    10. - Compound for use according to claim 9, wherein the compound is theobromine and is comprised of cocoa or chocolate.
    [11]
    11. - Compound for use according to any of claims 1-10, wherein the compound of the formula (I) is administered orally.
    [12]
    12. - Compound for use according to any of claims 1-11, wherein the compound of the formula (I) is administered at a dose between 100 mg / day and 400 mg / day.
    [13]
    13. - Compound for use according to claim 12, wherein the compound of the formula (I) is administered at a dose of 200 mg / day.
    [14]
    14. - Composition comprising the compound defined in any of claims 1-13, for use in the treatment and / or prevention of xanthine urolithiasis.
    [15]
    15. - Compound for use according to claim 14, wherein the composition is a pharmaceutical composition or a food supplement.
    类似技术:
    公开号 | 公开日 | 专利标题
    ES2622504T3|2017-07-06|New therapeutic approaches for the treatment of Alzheimer's disease and related disorders through an angiogenesis modulation
    ES2241350T3|2005-10-16|MEDICATION TO TREAT OBSTRUCTIVE CHRONICONEUMOPATHY BRONCHONEUMOPATHY.
    ES2399846T3|2013-04-03|MPO inhibitors for the treatment of Huntington's disease and multisystemic atrophy
    ES2531983T3|2015-03-23|Composition and method of treatment of cognitive impairments in individuals with Down syndrome
    JPWO2004096274A1|2006-07-13|Intra-airway administration
    Colliou et al.2017|Oxalate nephropathy following vitamin C intake within intensive care unit
    US20200282024A1|2020-09-10|Formulations for compound delivery
    KR20130014534A|2013-02-07|Use of meloxicam for the long-term treatment of kidney disorders in cats
    US10583105B2|2020-03-10|Compositions and methods for neuroprotection and treatment of neurodegeneration
    ES2728434B2|2020-02-24|Xanthine Crystallization Inhibitors
    WO2018218143A1|2018-11-29|Aryl hydrocarbon receptor | agonists for the prevention and treatment of inflammatory disorders
    PT3119201T|2018-06-15|Sildenafil solutions and methods of making and using same
    ES2297536T3|2008-05-01|PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF RENAL DYSFUNCTIONS.
    JP2000517331A|2000-12-26|Drugs containing lorunoxicam and disodium salt of EDTA
    ES2365429B1|2012-09-06|SOLUTION FOR PERITONEAL DIALYSIS
    US20200093772A1|2020-03-26|Substantially sodium free diclofenac potassium oral solutions
    RU2714257C2|2020-02-13|Composition, in stable condition, single-stranded nucleic acid molecule which suppresses expression of gene tgf-β1
    ES2552706B1|2016-09-13|THEOBOBROMINE AND ITS DERIVATIVES FOR THE TREATMENT OR PREVENTION OF RENAL LITHIASIS
    IL271836D0|2020-02-27|Use of edaravone in oral treatment of oxidative-stress mediated neurodegenerative disorders
    US20150290176A1|2015-10-15|Use of mtor inhibitors to treat vascular cognitive impairment
    BRPI0718199A2|2013-11-12|COMPOSITION AND METHODS FOR STABILIZING A MAMMAL'S BREATHING RATIO, AND INCREASING MINUTE VENTILATION AT AN INDIVIDUAL'S NUCLEUS TRACTUS SOLITARIUS RESPIRATORY CONTROL CENTERS.
    US20140187638A1|2014-07-03|Phenylbutyrate in rectal form for the treatment of a motor neuron disease or a metabolic disease
    KR100574378B1|2006-04-26|Use of 2-amino-6-trifluoromethoxy-benzothiazole for preventing or treating cerebellum dysfunction
    KR100379596B1|2003-04-10|The method of preparing for urinary calculus lithiasis for treatment
    JP5408261B2|2014-02-05|Choline salt of succinic acid for the treatment of depression, anxiety, schizophrenia, sleep disorders, and epilepsy
    同族专利:
    公开号 | 公开日
    ES2728434B2|2020-02-24|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    WO2015181412A1|2014-05-29|2015-12-03|Universitat De Les Illes Balears|Theobromine or its derivatives for the treatment or prevention of renal lithiasis|
    法律状态:
    2019-10-24| BA2A| Patent application published|Ref document number: 2728434 Country of ref document: ES Kind code of ref document: A1 Effective date: 20191024 |
    2020-02-24| FG2A| Definitive protection|Ref document number: 2728434 Country of ref document: ES Kind code of ref document: B2 Effective date: 20200224 |
    优先权:
    申请号 | 申请日 | 专利标题
    ES201830385A|ES2728434B2|2018-04-20|2018-04-20|Xanthine Crystallization Inhibitors|ES201830385A| ES2728434B2|2018-04-20|2018-04-20|Xanthine Crystallization Inhibitors|
    [返回顶部]