ES2366900T3 - USE OF 2,5-DIHYDROXIBENCEN DERIVATIVES FOR THE TREATMENT OF ARTHRITIS AND PAIN. - Google Patents

Abstract

Use of a compound selected from the group consisting of: 2- (acetyloxy) -5-hydroxybenzenesulfonic acid; 5- (acetyloxy) -2-hydroxybenzenesulfonic acid; 2,5-bis (acetyloxy) benzenesulfonic acid; 2- (acetyloxy) -5-hydroxybenzenehomosulfonic acid; 5- (acetyloxy) -2-hydroxybenzenehomosulfonic acid; 2,5-bis (acetyloxy) benzene sulfosulfonic acid; and pharmaceutically acceptable salts thereof, in the manufacture of a medicament for the treatment and / or prophylaxis of a disease selected from arthritis and pain.

Description

RELATED APPLICATIONS

This application claims the priority benefit of ES application No. P200602217, filed on August 16, 2006 and of ES application No. P200701855, filed on July 2, 2007.

FIELD OF THE INVENTION

The invention relates to the use of 2,5-dihydroxybenzene derivatives and their pharmaceutically acceptable salts for the treatment of certain diseases, specifically, for the treatment of pain and arthritis, by administering a compound that includes at least one compound of 2. , 5-dihydroxybenzene or a pharmaceutically acceptable salt thereof and, optionally, at least one therapeutic agent.

BACKGROUND OF THE INVENTION

Arthritis is a usually chronic condition that causes stiffness, pain and sometimes joint inflammation (includes osteoarthritis, rheumatoid arthritis, gouty arthritis, lupus-related arthritis and the like).

Pain is an unpleasant emotional (subjective) and sensory (objective) experience associated with an injury. It is the main reason why patients request medical attention.

WO2005 / 023305 A (Inpharamtica LTD; Allen J.M; overington J.P) (2005.03.17) describes the use of sultosyl acid for the treatment of arthritis and pain.

WO2005 / 013949 A (Allergan Inc; Jiang G.L, Yuang Y.) 2005.02.17) refers to the use of mixtures comprising sultosyl acid for the treatment of cachexia.

Compositions and methods for treating and preventing inflammatory diseases such as arthritis are described in the CA database of Chemical Abstracts, Columbus Ohio. US Hunter, W.L .: "Methods and pharmaceutical compositions using antimicrotubule agents for treating multiple sclerosis and other inflammatory diseases" ;; XP002456582 derived from the STN database, accession number 2002.960660. According to this database, the use of 3- (2,5-dihydroxyphenyl) methyl ester of propenoic acid is described.

The in vitro activity of piperazine sultosylate and compounds such as dobesilate salts are described by Dayrens P. et al: "Anti-inflammatory and immunostimulant activities of six sulfur compounds-four benzenesulphonates levamisole, and pyritinol hydrochloride-Assayed in mouse cell activation studies" ; Arzeneimittel Forschung. Drug Reasearc, ECV Editio Cantor Verlag, Aulendorf, DE, vol. 33 (I), No. 3, 1983, pages 372-377, XP001208316 ISSN: 00044172.

WO90 / 11759 A (Stuker G., 1990.10.18) and US-A-4513007 (De Courtner A. et al.), (1985.04.23) describe the treatment of arthritis and pain using compounds such as calcium dobesilate or other salts thereof.

Therefore, and despite recent scientific advances and knowledge about the etiology of the diseases described in this invention, there are no really effective treatments for those diseases.

SUMMARY OF THE INVENTION

The inventors have surprisingly found that 2,5-dihydroxybenzene derivatives and their pharmaceutically acceptable salts are useful for making medicaments for treating pain and arthritis.

Therefore, a first aspect of the present invention relates to the use of a compound sealed from the group consisting of:

 2- (acetyloxy) -5-hydroxybenzenesulfonic acid;

 5- (acetyloxy) -2-hydroxybenzenesulfonic acid;

2,5-bis (acetyloxy) benzenesulfonic acid;

2- (acetyloxy) -5-hydroxybenzenehomosulfonic acid;

5- (acetyloxy) -2-hydroxybenzenehomosulfonic acid;

2,5-bis (acetyloxy) benzene sulfosulfonic acid;

and pharmaceutically acceptable salts thereof,

in the manufacture of a medicament for the treatment and / or prophylaxis of a disease selected from arthritis and pain.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1. Inflammatory bowel disease

Effect of potassium 2,5-diacetoxybenzenesulfonate on body weight loss in mice with experimentally induced inflammatory bowel disease in a model applicable to the evaluation of treatments for ulcerative colitis and Crohn's disease. Mice were subjected to two 7-day cycles of exposure to sodium dextran sulfate (DSS) (day 1 to 7 and day 14 to 21) in drinking water separated by 7 days in which normal water was provided ( from 7 to 14). One group was treated with vehicle (0.9% NaCl), another with Solu-Medrol (10 mg / kg / day im), and the other two groups with potassium 2,5-diacetoxybenzenesulfonate (DABS), one of them with 100 mg / kg / day ip and the others with 125 mg / kg / day orally (p.o.). Body weight was normalized at day 0. Data are expressed as mean ± SD of the percentage of baseline weight (day 0) of 10 mice per group. All treatments had a significant effect on body weight compared to the vehicle treated group.

Figure 2. Inflammatory bowel disease

Effect of potassium 2,5-diacetoxybenzenesulfonate on the clinical disease score in mice with experimentally induced inflammatory bowel disease in an applicable model for the evaluation of treatments for ulcerative colitis and Crohn's disease. Mice were subjected to two 7-day cycles of exposure to sodium dextran sulfate (DSS) (day 1 to 7 and day 14 to 21) in drinking water separated by 7 days in which normal water was provided ( from 7 to 14). One group was treated with vehicle (0.9% NaCl), another with Solu-Medrol (10 mg / kg / day im), and the other two groups with potassium 2,5-diacetoxybenzenesulfonate (DABS), one of them with 100 mg / kg / day ip and the other with 125 mg / kg / day orally (p.o.). The data are expressed as mean ± SD of the clinical score of the disease continuously obtained from 10 mice per group.

Figure 3. Inhibition of mitogenesis induced by fibroblast growth factor 1 in quiescent cultures of Balb / c 3T3 fibroblasts by calcium 2-acetoxy-5-hydroxybenzenesulfonate (2A-5HBS) and potassium 2,5-dihydroxybenzenesulfonate (DHBS) .

Figure 4. Inhibition of mitogenesis induced by fibrolasts 1 growth factor in quiescent cultures of Balb / c 3T3 fibroblasts by potassium 5-acetoxy-2-hydroxybenzenesulfonate (5A-2HBS) and potassium 2,5-dihydroxybenzenesulfonate (DHBS) .

Figure 5. Inhibition of mitogenesis induced by fibroblast growth factor 1 in quiescent cultures of Balb / c 3T3 fibroblasts by potassium 2,5-diacetoxybenzenesulfonate (DABS) and potassium 2,5-dihydroxybenzenesulfonate (DHBS).

Figure 6. Co-crystallized 2-acetoxy-5-hydroxybenzenesulfonic acid with fibroblast growth factor 1. The electron density of the compound, with contours at 1 (panel C), allows the location and determination of the orientation of the compound with respect to the protein (panels A and B), as well as affirming that the compound retains the acetoxyl group in position 2 when it binds to the protein. The compound occupies a place that is very close to that described occupied by 2,5-dihydroxybenzenesulfonic acid, whose aromatic ring forms a cation- bond with the group N of lysine 132, which is marked on panel A as a reference . Panel B shows, in the form of a mesh, the volume of Van der Waals of 2-acetoxy-5-hydroxybenzenesulfonic acid, superimposed with its bar-shaped representation. In panels A and B, the surface of the protein is colored according to its electrostatic potential (light gray: negative charge; dark gray: positive charge; white: lack of charge).

Figure 7. Co-crystallized 5-acetoxy-2-hydroxybenzenesulfonic acid with fibroblast growth factor 1. The electron density of the compound, with contours at 1 (panel C), allows the location and determination of the orientation of the compound with respect to the protein (panels A and B), as well as affirming that the compound retains the acetoxyl group at position 5 when it binds to the protein. The compound occupies a place that is very close to that described occupied by 2,5-dihydroxybenzenesulfonic acid, whose aromatic ring forms a cation- bond with the group N of lysine 132, which is marked on panel A as a reference . Panel B shows, in the form of a mesh, the volume of Van der Waals of the 2-acetoxy-5-hydroxybenzenesulfonic acid superimposed with its bar-shaped representation. In panels A and B, the surface of the protein is colored according to its electrostatic potential (light gray: negative charge; dark gray: positive charge; white: lack of charge).

Figure 8. Co-crystallized 2,5-diacetoxybenzenesulfonic acid with fibroblast growth factor 1. The electron density of the compound, with contours at 1 (panel C), allows the location and determination of the orientation of the compound with respect to the protein ( panels A and B), as well as affirming that the compound retains the acetoxyl groups at positions 2 and 5 when bound to the protein. The compound occupies a place that is very close to that described occupied by 2,5-dihydroxybenzenesulfonic acid, whose aromatic ring forms a cation- bond with the group N of lysine 132, which is marked on panel A as a reference . Panel B shows, in the form of a mesh, the volume of Van der Waals of the 2,5-diacetoxybenzenesulfonic acid superimposed with its bar-shaped representation. In panels A and B, the surface of the protein is colored according to its electrostatic potential (light gray: negative charge; dark gray: positive charge; white: lack of charge).

DETAILED DESCRIPTION OF THE INVENTION

As used in the specification, it should be understood that, unless otherwise specified, the following terms shall have the meanings set forth below:

The term "patient" refers to animals, preferably mammals, and more preferably humans, and includes men and women, children and adults.

The term "effective amount" refers to the amount of the compound and / or composition effective to achieve the desired purpose.

The terms "treat" or "treatment" refer to the use of the compounds or compositions of the present invention, prophylactically to avoid the symptoms of disease or disorder, or therapeutically to improve an existing condition.

The term "therapeutic agent" includes any active agent that can be used to treat or prevent a disease described herein. "Therapeutic agents" includes, but are not limited to, corticosteroids, antibiotics, analgesics, alpha-adrenergic blockers, beta-adrenergic agonists, anticholinergics, 5-alpha-reductase inhibitors, antiandrogens, oral contraceptives, immunomodulators, immunosuppressants, antiangiogens, bronchodilators, modifiers of leukotriene, aminosalicylates, anesthetics, non-steroidal anti-inflammatories, antiparasitic agents, antioxidants, proton pump inhibitors, H2 receptor antagonists, solubilized interleukin receptor therapy, intramuscular gold, cytotoxic agents, chemotherapeutic agents and combinations of two or more thereof.

A therapeutic agent includes pharmaceutically acceptable salts, prodrugs and pharmaceutical derivatives thereof.

The term "pain" refers to an unpleasant emotional (subjective) or sensory (objective) experience associated with an injury.

The term "arthritis" refers to a condition, usually chronic, that causes stiffness, pain and, sometimes, joint inflammation; includes osteoarthritis, rheumatoid arthritis, polyarthritis, gouty arthritis, lupus-related arthritis, psoriasis-related arthritis and the like).

The term "topical" refers to the administration of a compound by administering it on the surface of the body and includes, but is not limited to, transdermal administration and administration through the mucosa.

The term "transdermal" refers to the administration of a compound that enters the bloodstream through the skin.

The expression "through the mucosa" refers to the administration of a compound that enters the bloodstream through the mucosa tissue.

The term "parenteral" refers to the administration of a compound by a subcutaneous, intravenous, intramuscular, intracardiac, intradermal, intraperitoneal, intrathecal or intrasternal injection; and also includes local or systemic infusion techniques.

The terms "penetration enhancement" or "permeation enhancement" refer to an increase in the permeability of the skin or mucosa tissue for a pharmacologically active compound such that the speed and / or amount of said compound is increased that penetrates into, or through, the skin or mucosal tissue.

"Excipients" or "vehicles" refers to vehicle materials suitable for compound administration, and includes any material known in the art such as, for example, any liquid, gel, solvent, liquid diluent, solubilizer or the like that is not toxic and that does not interact harmfully with any component of the composition.

The term "sustained release" refers to the release of an active compound and / or composition such that blood levels of the active compound are maintained within a desirable therapeutic range for a period of time. The sustained release formulation can be prepared using any conventional method known to a person skilled in the art to obtain the desired release characteristics.

The present invention relates to the use of a compound selected from the group consisting of:

2- (acetyloxy) -5-hydroxybenzenesulfonic acid;

5- (acetyloxy) -2-hydroxybenzenesulfonic acid;

2,5-bis (acetyloxy) benzenesulfonic acid;

2- (acetyloxy) -5-hydroxybenzenehomosulfonic acid;

5- (acetyloxy) -2-hydroxybenzenehomosulfonic acid; 2,5-bis (acetyloxy) benzene sulfosulfonic acid;

and pharmaceutically acceptable salts thereof,

in the manufacture of a medicament for the treatment and / or prophylaxis of a disease selected from arthritis and pain.

Preferred compounds are those selected from 2- (acetyloxy) -5-hydroxybenzenesulfonic acid, 5 (acetyloxy) -2-hydroxybenzenesulfonic acid and 2,5-bis (acetyloxy) benzenesulfonic acid.

In a particular embodiment, the arthritis is selected from osteoarthritis, rheumatoid arthritis, polyarthritis, gouty arthritis, lupus-related arthritis, psoriasis-related arthritis, infectious arthritis including viral, parasitic and bacterial arthritis.

The invention provides compositions comprising at least one compound of those defined above and at least one additional therapeutic agent including, but not limited to, a chemotherapeutic agent, a corticosteroid, an antibiotic, an analgesic, an alpha-adrenergic blocker, a beta agonist. -adrenergic, an anticholinergic, a 5-alpha-reductase inhibitor, an antiandrogen, an immunomodulator, an immunosuppressant, an antiangiogenic such as anti-VEGF, anti-FGF, anti-HGF and anti-EFG; a leukotriene modifier, an aminosalicylate, an anesthetic, a non-steroidal anti-inflammatory, an antiparasitic, a solubilized interleukin receptor therapy, intramuscular gold, a cytotoxic, an antioxidant and combinations of two or more thereof.

The compounds used in the invention may optionally be used together with one or more additional therapeutic agents such as a chemotherapeutic agent, a corticosteroid, an antibiotic, an analgesic, an alpha-adrenergic blocker, a beta-adrenergic agonist, an anticholinergic, an inhibitor of 5-alpha-reductase, an antiandrogen, an immunomodulator, an immunosuppressant, an antiangiogenic such as anti-VEGF, anti-FGF, anti-HGF and anti-EFG; a leukotriene modifier, an aminosalicylate, an anesthetic, a non-steroidal anti-inflammatory, an antiparasitic, a solubilized interleukin receptor therapy, intramuscular gold, a cytotoxic, an antioxidant and combinations of two or more thereof.

The compounds used in the invention can be synthesized by one skilled in the art using conventional or commercially available methods. The synthesis of these compounds is disclosed, for example, in US Pat. No. 5,082,941; and in "The Merck Index" 13th edition, Merck & Co., R. Railway, NJ., USA, 2001; U.S. patents No. 5,082,841, 4,814,110, 4,613,332 and 4,115,648.

The scope of the present invention covers any salt thereof, especially any pharmaceutically acceptable salt of the compound. The phrase "pharmaceutically acceptable salts" includes metal salts

or the addition salts that can be used in pharmaceutical forms. For example, the pharmaceutically acceptable salts of the compounds provided herein may be acid addition salts, base addition salts or metal salts, and may be synthesized from the original compounds containing a basic or acidic residue using methods conventional chemicals Generally, these salts are prepared, for example, by reacting base or free acid forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of both. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. Examples of acid addition salts include mineral acid addition salts such as, for example, hydrochloride, hydrobromide, iodhydrate, sulfate, nitrate, phosphate, organic acid addition salts such as, for example, acetate, maleate, fumarate. , citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and ptoluenesulfonate. Examples of base addition salts include inorganic salts such as, for example, ammonium salts and organic alkaline salts such as, for example, diethylamine, ethylenediamine, ethanolamine, N, N-dialkyleneolamine, triethanolamine, glutamine and basic amino acid salts. Examples of metal salts include, for example, sodium, potassium, calcium, magnesium, aluminum and lithium salts.

The term "pharmaceutically acceptable" refers to molecular entities and physiologically tolerable compositions that typically do not produce an allergic or similar adverse reaction, such as gastric discomfort, vertigo and the like, when administered to a human being. Preferably, as used herein, the term "pharmaceutically acceptable" means that it is approved by a federal or state government regulatory agency or listed in the US Pharmacopoeia, or other generally recognized pharmacopoeia, as suitable for use. in animals and, more particularly, in humans.

It will be obvious to those skilled in the art that the scope of the present invention also comprises salts that are not pharmaceutically acceptable as possible means of obtaining pharmaceutically acceptable salts.

The pharmaceutically acceptable salts of the compounds used in the invention can be prepared from organic or inorganic acids or bases by conventional procedures by reacting an appropriate acid or base with the compound.

In a particular embodiment of the invention, the 2,5-dihydroxybenzene derivatives of the invention can optionally be used in combinations with each other. Such combinations may be in the same formulation or in formulations that would be used sequentially.

The 2,5-dihydroxybenzene compounds are preferably formulated in the form of potassium, calcium, magnesium and ethylamine salts. The scope of the present invention comprises any pharmaceutically acceptable salt of the compound. The phrase "pharmaceutically acceptable salts" includes metal salts or addition salts that can be used in pharmaceutical forms. Pharmaceutically acceptable salts of 2,5-dihydroxybenzene compounds can be prepared from organic or inorganic acids or bases by conventional procedures by reacting the appropriate acid or base with the compound.

The compounds used in the invention can be used at a level of about 1 mg / kg of weight to about 200 mg / kg of weight without evidencing toxicity.

Corticosteroids include, but are not limited to, both topical corticosteroids (in creams, ointments, ointments or gels) as well as intra-articular and systemic inhalations such as triamcinolone acetate and the like, systemic corticosteroids such as, for example, prednisone and the like.

Immunosuppressants and chemotherapeutic agents include, but are not limited to, topical or systemic such as cyclosporine, methotrexate, azathioprine, leflunomide and vincristine.

Immunomodulators include, but are not limited to, interferon alfa.

Leukotriene modifiers include, but are not limited to, for example montelukast, zafirlukast, zileuton, chromolin, nedocromil.

Aminosalicylates include, but are not limited to, sulfasalazine, sulfapyridine, olsalazine, mesalamine, balsalazide; antihistamines such as diphenhydramine, hydroxyzine and the like.

Antiangiogens such as bevacizumab.

Bismuth salts.

Proton pump inhibitors include, but are not limited to, omeprazole, lansoprazole, pantoprazole.

H2 receptor antagonists include, but are not limited to, cimetidine, ranitidine.

Antiparasitic agents such as hydrochloroquine.

Pain relievers such as codeine, dihydrocodeine, morphine, oxidocona.

Antimicrobial compounds include, but are not limited to, macrolides such as, for example, azithromycin, clarithromycin, dithromycin, erythromycin, milbemycin, troleandomycin and the like; monobactams such as, for example, aztreonam and the like; tetracyclines such as, for example, demeclocycline, doxycycline, minocycline, oxytetracycline, tetracycline and the like; aminoglycosides such as, for example, amikacin, gentamicin, kanamycin, neomycin, netilmicin, paromomycin, streptomycin, tobramycin and the like; carbacephems such as, for example, loracarbef and the like; carbapene such as, for example, ertapenem, imipenem, meropenem and the like; penicillins such as, for example, amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, naphcillin, penicillin, piperacillin, ticarcillin and the like; polypeptides such as, for example, bacitracin, colistin, polymyxin B and the like; beta-lactamase inhibitors; cephalosporins such as, for example, cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, cefadroxil, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefazolin, cefixime, cephalexin, cefepime, and the like; quinolones such as, for example, ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, trovafloxacin and the like; streptogramins; sulfonamides such as, for example, mefanide, prontosil, sulfacetamide, sulfamethizol, sulfanilamide, sulfasalazine, sulfisoxazole, trimethoprim, trimethoprim-sultamethoxazole and the like; and combination medications such as, for example, sulfamethoxazole and trimethoprim and the like. Suitable antimicrobial compounds of the invention are described more fully in the literature, such as in Goodman and Gilman, "The Pharmacological Basis of Therapeutics" (9th edition), McGraw-Hill, (1996); Merck Index on CD-ROM, 13th edition; STN Express, phar file and registry file, whose descriptions are incorporated as a reference to this report in its entirety.

Suitable non-steroidal anti-inflammatory drugs (NSAIDs) include, but are not limited to, acetaminophen, acemetacin, aceclofenac, alminoprofen, amfenac, bendazac, benoxaprofen, bromfenac, buclotoxic acid, butibuphene, carprofen, cinmetacin, chlopyra, diclofenac, fellococcococococcal, diclofenac, phenocococococcal, phenococococcal, phenococococcal, phenococococcal, phenococococcal, phenococococcal, phenococococcal, phenocodococolococcal, phenocodococolococcal, phenocodococolococrylic acid , fenbufen, fenoprofen, fentiazac, flunoxaprofen, flurbiprofen, ibufenac, ibuprofen, indomethacin, isofezolac, isoxepaco, indoprofen, ketoprofen, lonazolac, loxoprofen, methiazinic acid, mofezolaco, pyrophenolaproxin, pyrophenolaproxin, pyrophenolaproxin, pyrophenolaproxin, pyrophenolaproxin, pyrophenolaproxin, pyrophenolaproxin, pyrophenolaproxin, pyrophenolaproxin, pyrophenolane, pyrophenolaproxin, pyrophenolaproxin, pyrophenolane, pyrophenolane, pyrophenolane, pyrophenolane, pyrophenolaproxin , sulindaco, suprofen, suxibuzone, thiaprofenic acid, tolmetine, xenbucina, ximoprofen, zaltoprofen, zomepiraco, aspirin, acemetcina, bumadizona, clidanaco, diflunisal, empenamic acid, fendosal, flufenamic acid, flunixin, methic acid, gentisamic acid , mesalamine, prodrugs thereof and if Millar Suitable NSAIDs are described more fully in the literature as in Goodman and Gilman, "The Pharmacological Basis of Therapeutics" (9th edition), McGraw-Hill, 1995, pages 617-657; the Merck Index on CD-ROM, (13th edition); and in U.S. Pat. No. 6,057,347 and 6,297,260 assigned to NitroMed Inc., whose descriptions are incorporated herein by reference in their entirety.

In some embodiments, the NSAIDs are acetaminophen, diclofenac, flurbiprofen, ibuprofen, indomethacin, ketoprofen, naproxen or aspirin.

Suitable topical anesthetics include, but are not limited to, lidocaine.

When administered separately, the 2,5-dihydroxybenzene compounds employed in the invention can be administered at about the same time as part of a complete treatment regimen, that is, in the form of combination therapy. The term "approximately at the same time" includes the administration of the 2,5-dihydroxybenzene compound simultaneously, sequentially, at the same time, at different times during the same day or on different days, provided it is administered as part of a complete treatment regimen, that is, a combination therapy or a therapeutic cocktail.

When administered alone, the compounds employed in the present invention can be administered in combination with pharmaceutically accepted carriers and at the dosages described herein. When the compounds are administered in the form of a combination of at least one compound of 2,5-dihydroxybenzene and / or at least one additional therapeutic agent, a combination with one or more additional compounds known to be effective for pathology can be used. specific established as a goal for treatment. Different therapeutic agents and / or additional compounds may be administered simultaneously to, after, or before administering the 2,5-dihydroxybenzene compound.

Pharmaceutical compositions containing the compounds of the invention may be presented in any form of administration suitable, for example, for systemic, transdermal, oral, buccal, parenteral, topical, rectal, intravaginal administration or by inhalation; therefore, they will include the acceptable pharmaceutical excipients necessary to formulate the desired form of administration.

The compositions comprise an effective amount of 2,5-dihydroxybenzene compounds of about 0.001 to about 30%. In addition, the composition comprises a pharmaceutically acceptable carrier. Generally, the carrier is organic and may contain diluted or dispersed 2,5-dihydroxybenzene compounds. Lotions, creams, solutions, gels and solids are the usual physical forms of the composition.

The subject treated with the medicament of the invention is an animal, preferably a mammal and more preferably a human being. The main object of the present invention is directed to the treatment or prevention of the described diseases, mainly in humans. Second, the present invention can be used for the treatment

or the prevention of such diseases in pets and farm animals, without limitation, cattle, horses and pigs.

The medicament of the present invention can be administered by any of the routes commonly used to administer medicaments. Such pathways include, but are not limited to, topical, transdermal, oral, oral, parenteral, inhalation, rectal, intravaginal, intraocular, otic or intraarticular administration for the treatment of arthritis or pain.

The parenteral route of administration can be intraperitoneal, intravenous, intraarterial, perioral, subcutaneous, intramuscular, etc.

The compositions can be administered in conventional dosage forms prepared by the combination of pharmacologically standardized "vehicles." These combinations involve procedures such as mixing, granulation, compression and dissolution in suitable ingredients. The form and nature of the pharmacologically acceptable vehicle are related to the active ingredient with which they are mixed and the route of administration.

The term "vehicle", as used herein, refers to the diluents and excipients used to prepare the pharmaceutical composition. The term "pharmacologically acceptable" refers to the requirements described in the Pharmacopoeia related to the manufacture and use of drugs in animals, and especially in humans.

Pharmacologically acceptable vehicles can be liquid or solid. The compositions of the invention can be administered orally. To this end, the pharmaceutical composition may be prepared in liquid form such as solutions, syrups or suspensions, or it may be formulated as a product to reconstitute with water or other vehicles before administration. Liquid formulations can be prepared using conventional means with pharmacologically acceptable additives such as suspending agents (sorbitol), non-aqueous vehicles (oil or ether), emulsifying agents (lecithin) and preservatives (sorbic acid). The pharmaceutical composition may be in the form of tablets, capsules or aggregates prepared using conventional methods with pharmacologically acceptable excipients such as binding agents (polyvinylpyrrolidone or hydroxypropylcellulose), extenders (lactose or microcrystalline cellulose), lubricants (magnesium stearate or talc), disintegrants ( potato starch) or wetting agents (sodium lauryl sulfate). The tablets may be coated using pharmaceutically acceptable methods.

Compositions for oral or oral administration may be formulated such that they have a controlled release of the active compound. Such formulations may include one or more continuous release agents such as glycerol monostearate, glycerol distearate and wax.

Pharmaceutical compositions containing the active ingredient of the invention can also be administered topically on the epidermis, oral cavity, eye, ear, nasal cavity or urethral, vaginal or rectal mucosa. Compositions for use in topical administration include liquid or gel preparations for administration on the skin such as creams, ointments, liniments or pastes and drops suitable for delivery to the eye, ear or nose. According to the invention, creams, drops, liniments, lotions, ointments and pastes are liquid or semi-solid compositions for external administration. These formulations can be prepared by mixing the active ingredient in powder form, alone or in solution or suspension in an aqueous or non-aqueous fluid with a fatty or non-fatty base. The base may comprise complex carbohydrates such as glycerol, various forms of paraffin, beeswax, a mucilage, a mineral or edible oil or fatty acids, or a macrogel. The formulations may additionally comprise suitable emulsifying agents such as surfactants, and suspending agents such as agar, vegetable gums, cellulose derivatives and other ingredients such as preservatives, antioxidants, etc.

Lotions and drops include those suitable for administration on the skin or supply to the eye. Lotions and eye drops may be formulated in sterile aqueous solution; oil solutions or suspensions can be prepared by diluting the active ingredient in a suitable aqueous solution. Such solutions may optionally contain a suitable bactericide, fungicide, preservative and surfactant. Lotions and liniments for administration on the skin may also contain dehydrating agents such as alcohol and / or wetting agents such as glycerol, an oil or a fatty acid.

The formulations can also be administered nasally or by inhalation. For nasal or inhalation administration, the formulations are conveniently supplied in the form of an aerosol spray in pressurized containers or a nebulizer with the use of a suitable propellant, for example, dichlorodifluoromethane, trichlorotrifluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas . In the case of a pressure aerosol, the dosage unit can be determined by providing a valve to release a specific amount. Capsules and cartridges of, for example, gelatin can be formulated for use in an inhaler, providing a valve for releasing a specific amount. Capsules and cartridges of, for example, gelatin can be formulated for use in an inhaler, containing a powder mixture of the compound and a suitable powder base such as lactose or starch.

The compounds of the invention can also be formulated for delayed release. Such long-acting formulations can be administered by implant (for example, subcutaneous or intramuscular) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, in the form of an emulsion in an acceptable oil) or ion exchange resins, or sparingly soluble derivatives, for example, in the form of a sparsely salt. soluble.

In a particular embodiment of the invention, the compounds employed in the invention are administered at least once a week, more preferably at least once a day, even more preferably twice a day. In another particular embodiment, the compounds are administered for a period of at least about one week, more preferably for a period of at least about four weeks.

The duration of treatment will typically depend on the particular condition, its severity, the condition of the patient and the like, and will be readily determined by one skilled in the art. Illustrative therapeutic treatments include 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 3.5 months, 4 months, 4 , 5 months, 5 months, 6 months, 9 months, one year, or more as needed.

When treating a subject suffering from a disorder described herein, treatment may continue until at least 10% improvement of a symptom associated with the condition is made. In other embodiments, the treatment is continued until the subject in need of said treatment experiences an improvement of at least about 20%, at least about 30%, at least about 40%, preferably at least about 50% , preferably at least about 60%, more preferably at least about 70%, more preferably at least about 80%, even more preferably 90% or more of a symptom associated with a disorder described herein.

In a particular embodiment of the invention, the compound of the formula employed in the invention is administered at least once a week. In other embodiments, the compound is administered at least once a day. In still other embodiments, the compound is administered twice daily. In another particular embodiment, the compound is administered for a period of at least about a week. In other embodiments, the compound is administered for a period of at least about four weeks.

The therapeutic amounts can be determined empirically and will vary with the condition being treated, the subject, the components of the particular formulation, the dosage form and the like.

In a particular embodiment, the compound is present in a pharmaceutical composition in an amount of at least about 1% w / w. In other embodiments, the compound is present in a pharmaceutical composition in an amount of at least about 2.5% w / w, at least about 5% w / w, at least about 10% w / w, or at least about 15% w / w.

In one embodiment, the 2,5-dihydroxybenzene compounds can be administered in an amount of about 0.05 g per day to about 50 g per day. In particular embodiments, the 2,5-dihydroxybenzene compounds can be administered in an amount of about 0.10 g per day to about 25 g per day. In more particular embodiments, the 2,5-dihydroxybenzene compounds can be administered in an amount of about 0.25 g per day to about 10 g per day. In a more particular embodiment, the 2,5-dihydroxybenzene compounds can be administered in an amount of about 0.5 g per day to about 5 g per day. In an even more particular embodiment, the 2,5-dihydroxybenzene compounds can be administered in an amount of about 0.75 g per day to about 2.5 g per day. In another particular embodiment, the 2,5-dihydroxybenzene compounds can be administered in an amount of about 1 g per day to about 1.5 g per day. Particular amounts of 2,5-dihydroxybenzene compounds may be administered as a single dose once a day, or in multiple doses several times a day, or in the form of a sustained release formulation. In one embodiment of the invention, the 2,5-dihydroxybenzene compounds are administered in the form of approximately 50 g, 25 g, 10 g, 5 g, 1 g, 0.75 g, 0.5 g, 0, 25 g or 0.1 g once a day (qd). In another embodiment of the invention, the 2,5-dihydroxybenzene compounds are administered in the form of approximately 50 g, 25 g, 10 g, 5 g, 1 g, 0.75 g, 0.5 g, 0, 25 g or 0.1 g twice daily (bid). In another embodiment of the invention, the 2,5-dihydroxybenzene compounds are administered in the form of approximately 50 g, 25 g, 10 g, 5 g, 1 g, 0.75 g, 0.5 g, 0, 25 g or 0.1 g three times a day (tid). In another embodiment of the invention, the 2,5-dihydroxybenzene compounds are administered in the form of approximately 50 g, 25 g, 10 g, 5 g, 1 g, 0.75 g, 0.5 g, 0, 25 g or 0.1 g four times a day.

In particular embodiments, the 2,5-dihydroxybenzene compounds can be administered topically in a formulation comprising an amount of about 0.001% to about 30% (w / w) of the 2,5-dihydroxybenzene compounds. In a more particular embodiment, the 2,5-dihydroxybenzene compounds can be administered topically in a formulation comprising an amount of about 0.01% to about 20% (w / w) of the 2,5-dihydroxybenzene compounds . In an even more particular embodiment, the 2,5-dihydroxybenzene compounds can be administered topically in a formulation comprising an amount of about 0.1% to about 15% (w / w) of the compounds of 2, 5-dihydroxybenzene. In another particular embodiment, the 2,5-dihydroxybenzene compounds can be administered topically in a formulation comprising an amount of about 1% to about 5% (w / w) of the 2,5-dihydroxybenzene compounds. In an even more particular embodiment, the 2,5-dihydroxybenzene compounds can be administered topically in a formulation comprising an amount of about 2.5% to about 4% (w / w) of the compounds of 2, 5-dihydroxybenzene. The topical formulation comprising the 2,5-dihydroxybenzene compounds can be administered in the form of a single dose once a day, or multiple doses several times throughout the day. In one embodiment of the invention, the topical formulation comprising approximately 30%, 20%, 15%, 10%, 5%, 2.5%, 1%, 0.5%, 0.1% or 0.001% of the 2,5-dihydroxybenzene compound is administered four times a day. In another embodiment of the invention, the topical formulation comprising approximately 30%, 20%, 15%, 10%, 5%, 2.5%, 1%, 0.5%, 0.1% or 0.001% of the 2,5-dihydroxybenzene compounds are administered three times a day (tid). In yet another embodiment of the invention, the topical formulation comprising approximately 30%, 20%, 15%, 10%, 5%, 2.5%, 1%, 0.5%, 0.1% or 0.001 % of the 2,5-dihydroxybenzene compounds are administered twice daily (bid). In yet another embodiment of the invention, the topical formulation comprising approximately 30%, 20%, 15%, 10%, 5%, 2.5%, 1%, 0.5%, 0.1% or 0.001 % of the 2,5-dihydroxybenzene compounds are administered once daily (qd).

In still other embodiments, the invention provides a kit or package comprising a compound such as those used in the invention, in packaged form, accompanied by instructions for use. The compound may be packaged in any manner suitable for administration, provided that the package, when considered in conjunction with the instructions for administration, indicates the manner in which the compound is to be administered.

For example, a kit may comprise the compound in unit dosage form, together with instructions for use. For example, such instructions may indicate that administration of the compound is useful in the treatment of pain and / or arthritis. The compound can be packaged in any manner suitable for administration. For example, when the compound is in oral dosage form, for example it is in the form of a coated tablet, then the kit may comprise a sealed container of coated tablets, blister strips containing the tablets or the like.

Various embodiments can be easily conceived according to the foregoing, and would depend on the particular dosage form, the recommended dosage, the intended patient population and the like. The packaging can be in any form commonly used for the packaging of pharmaceutical products, and can use any of a number of features such as different colors, wraps, tamper-resistant packaging, blister packs or strips and the like.

The following non-limiting examples further describe and enable a person skilled in the art to make use of the present invention.

EXAMPLES OF THE INVENTION

Example 1. Preparation of lotions.

Lotions comprise from about 0.01% to about 30% of the compounds employed in the invention, from 1% to 25% of an emollient and the appropriate amount of water. Examples of emollients are:

I. Waxes and hydrocarbon oils such as mineral oil, petrolatum, paraffin, ceresin, microcrystalline wax, polyethylene and perhydrosqualene.

II. Silicone oils such as dimethylpolysiloxanes, methylphenylpolysiloxanes and water-soluble and alcohol-soluble silicone-glycol copolymers.

III. Triglycerides such as animal and vegetable fats and oils. Examples include, but are not limited to, castor oil, cod liver oil, corn oil, olive oil, almond oil, palm oil, sesame oil, cottonseed oil and soybean oil.

IV.

Acetoglyceride esters such as acetylated monoglycerides.

V.

Ethoxylated glycerides such as ethoxylated glycerol monostearate.

SAW. Alkyl esters of fatty acids having 10 to 20 carbon atoms. Methyl, isopropyl and butyl fatty acid esters are useful herein. Examples include, but are not limited to, hexyl laurate, isohexyl laurate, isohexyl palmitate, isopropyl palmitate, decyl oleate, isodecyl oleate, hexadecyl stearate, decyl stearate, isopropyl isostearate, diisopropyl adipate, adipate adipate diisohexyl, dihexyldecyl adipate, diisopropyl sebacate, lauryl lactate, myristoyl lactate and cetyl lactate.

VII. Alkenyl esters of fatty acids having 10 to 20 carbon atoms. Examples thereof include, but are not limited to, oil myristate, oil stearate and oil oleate.

VIII. Fatty acids that have 10 to 20 carbon atoms. Suitable examples include, but are not limited to, pelargonic, lauric, myristic, palmitic, stearic, isostearic, hydroxystearic, oleic, linoleic, ricinoleic, arachidonic, behenic and erucic acids.

IX.

Fatty alcohols having 10 to 20 carbon atoms. The alcohols of lauryl, myristoyl, palmitoyl, stearyl, isostearyl, hydroxy stearyl, oleyl, ricinoleyl, behenyl, erucilo and 2-octyldodecanol are suitable examples of fatty alcohols.

X.

Ethers of fatty alcohol. Ethoxylated fatty alcohols having 10 to 20 carbon atoms include, but are not limited to, lauryl, cetyl, stearyl, isostearyl, oleyl and cholesterol alcohols having 1 to 50 ethylene oxide groups or 1 to 50 oxide groups attached thereto of propylene.

XI Ether esters such as fatty acid esters of ethoxylated fatty alcohols.

XII. Lanolin and derivatives. Lanolin, lanolin oil, lanolin wax, lanolin alcohols, lanolin fatty acids, isopropyl lanolate, ethoxylated lanolin, ethoxylated lanolin alcohols, ethoxylated cholesterol, propoxylated lanolin alcohols, acetylated lanolin, acetylated lanolin alcohols, alcool linolates Lanolin, lanolin alcohol ricinoleate, lanolin alcohol ricinoleate acetate, lanolin hydrogenolysis and liquid and semi-solid laniline absorption bases are illustrative examples of lanolin derived emollients.

XIII Polyhydric alcohols and polyether derivatives. Propylene glycol, dipropylene glycol, polypropylene glycol 2000 and 4000, polyoxyethylene polypropylene glycols, glycerol, ethoxylated glycerol, propoxylated glycerol, sorbitol, ethoxylate sorbitol, hydroxypropylsorbitol, polyethylene glycol 200-6000, ethylene glycol 550, 750, ethylene glycol (100,000-5,000,000), polyalkylene glycols and derivatives, hexylene glycol (2-methyl-2,4-pentanediol), 1,3-butylene glycol, 1,2,6-hexanotriol, USP ethohexadiol (2-ethyl-1,3-hexanediol) and derivatives of

Trimethylolpropane polyoxypropylene are suitable examples.

XIV Esters of polyhydric alcohol. Monoacrylic and diacyl esters of ethylene glycol, monoacyl and diacyl esters of diethylene glycol, monoacrylic and diacyl esters of polyethylene glycol (200-6000), monoacyl and diacyl esters of propylene glycol, polypropylene glycol monostearate, polypropylene glycol monostearate ethylene glycol monostearate 2000 and glycerol diacyl, polyglycerol polyacrylic esters, ethoxylated glycerol monostearate, 1,3-butylene glycol monostearate, 1,3-butylene glycol distearate, polyoxyethylene polyol acyl ester, sorbitan acyl esters and polyoxyethylene sorbitan esters are examples.

XV. Waxes such as beeswax, spermaceti, myristoyl myristate and stearyl stearate.

XVI. Beeswax derivatives such as polyoxyethylene sorbitol beeswax. These are reaction products of beeswax with ethoxylated sorbitol of varying ethylene oxide content that forms a mixture of ethersters.

XVII. Vegetable waxes including, but not limited to, carnauba and candelilla waxes.

XVIII. Phospholipids such as lecithin and derivatives.

XIX. Sterols Examples include, but are not limited to, cholesterol and cholesterol acyl esters.

XX. Amides such as fatty acid amides, ethoxylated acyl amides and solid fatty acid alkanolamides.

Lotions of the invention further comprise 1% to 10% emulsifier. The emulsifiers can be anionic, cationic or non-ionic.

Examples of non-ionic emulsifiers include, but are not limited to: fatty alcohols having 10 to 20 carbon atoms, fatty alcohols having 10 to 20 carbon atoms condensed with 2 to 20 moles of ethylene oxide or propylene oxide, alkyl phenols of 6 to 12 carbons in the alkyl chain condensed with 2 to 20 moles of ethylene oxide, monoacyl and diacyl esters of ethylene glycol, in which the fatty acid contains 10 to 20 carbons, monoglycerides in which the fatty acid contains 10 to 20 carbons, diethylene glycol, polyethylene glycols of molecular weight 200 to 6,000, polypropylene glycol of molecular weight 200 to 3,000, glycerol, sorbitol, sorbitan, polyoxyethylene sorbitol, polyoxyethylene sorbitan and hydrophilic wax esters.

Suitable anionic emulsifiers include, but are not limited to, saponified fatty acids (soaps) with potassium, sodium or triethanolamine, in which the fatty acid contains from 10 to 20 carbons. Other suitable anionic emulsifiers include, but are not limited to, alkali metals, ammonium or ammonium substituted with alkyl sulfates, alkyl arylsulfonates and alkyl ethoxyether sulfonates having 10 to 30 carbons in the alkyl chain and 1 to 50 ethylene oxide units. Suitable cationic emulsifiers include quaternary ammonium and morpholinium and pyridinium compounds.

Some emollients described above also have emulsifying properties. When a lotion contains one of these emollients, an additional emulsifier is not necessary, although it may be included in the formulation.

The rest of the composition is water. Lotions are formulated by simply mixing all the components together. Preferably, the compounds employed in the invention are dissolved in the emollient and the resulting mixture is added to the water. Optional components such as emulsifier or customary additives may be included in the composition.

A thickening agent included at a level of 1% to 30% by weight of the composition is a common additive. Examples of suitable thickening agents are crosslinked carboxy polymethylene polymers, methyl cellulose, polyethylene glycols, gums and bentonite.

Example 2. Preparation of creams.

The compositions of the present invention can also be formulated in the form of a cream. Creams contain from about 0.001% to about 30% of the compounds employed in the invention, from 5% to 50% of an emollient and the appropriate amount of water. The emollients described above in example 1 are also suitable for cream formulation. Optionally, the cream may contain an emollient at a level of 3% to 50%. The emulsifiers described above in example 1 would also be suitable in this case.

Example 3. Preparation of solutions

The compositions of the present invention can also be formulated in the form of a solution. The solutions contain from about 0.001% to about 30% of the compounds employed in the invention and the appropriate amount of an organic solvent. The organic substances useful as a solvent or a part of the solvent system are the following: propylene glycol, polyethylene glycol (200-600), polypropylene glycol (425-2025), glycerin, sorbitol esters, 1,2,6-hexanotriol, ethanol, isopropanol, diethyl tartrate, butanediol and mixtures thereof. Such solvent systems may also contain water.

These compositions are administered on the skin in the form of a solution, or aerosol solutions are formulated and administered on the skin in the form of a spray. The aerosol compositions additionally contain 25% to 80% of a suitable propellant. Examples of propellants include, but are not limited to: chlorinated, fluorinated and fluorochlorinated low molecular weight hydrocarbons. Nitrous oxide and carbon dioxide can also be used as propellant gases. Enough quantity is used to eject the contents of the cartridge.

Example 4. Preparation of gels.

The gel-shaped composition could be obtained by simply adding a suitable thickening agent to the composition in the form of the solution described in example 3. Suitable thickening agents have already been described in example 1.

Gel formulations contain from about 0.001% to about 30% of the compounds employed in the invention, 5% to 75% of a suitable organic solvent, 0.5% to 20% of a suitable thickening agent and the necessary amount of water .

Example 5. Preparation of solids.

The compositions of the present invention can also be formulated in solid form. These forms have the shape of a bar intended for administration on the lips or other parts of the body. These compositions contain from about 0.001% to about 30% of the compounds employed in the invention and from 50% to 98% of an emollient such as described above. The composition may contain from 1% to 20% of a suitable thickening agent, such as those described in the previous examples and, optionally, emulsifiers and water.

Additives commonly found in topical compositions, such as preservatives (for example, methylparaben and ethylparaben), dyes and perfumes, may be included in any of the formulations described in Examples 1-5.

Example 6. Effect of 2,5-diketoxybenzenesulfonic acid on the treatment of inflammatory bowel disease induced in mice.

Induction of inflammatory bowel disease described below is a representative model of the evaluation of therapeutic strategies to treat Crohn's disease and ulcerative colitis. 7-8 week female mice of strain C57BL / 6J-664 were used. Inflammatory bowel disease (IBD) was induced by feeding the mice with sodium dextran sulfate (DSS, PM 40,000) dissolved in drinking water in 2 cycles. Each cycle consisted of 7 days with 3% DSS in drinking water separated by 7 days with normal water. A daily clinical evaluation of the animals was performed in which the body weight, the consistency of the feces and the presence of blood in the feces were determined. Therefore, the validated score of the clinical activity of the disease was evaluated with a scale of 0 to 6, considering the following parameters: stool consistency, presence

or absence of fecal blood and weight loss.

At the end of the first cycle of exposure to DSS, the mice were divided into the following treatment groups: vehicle injections (0.9% NaCl) were administered to a first group intraperitoneally (i.p). Another group received intramuscular injections of Solu-Medrol, a standard IBD treatment, at a dose of 10 mg / kg / day. I.p. injections were administered to a third group. of potassium 2,5-diacetoxybenzenesulfonate (DABS, 100 mg / kg / day). The last group was treated orally with 125 mg / kg per day of DABS.

As shown in Figure 1, the weight loss caused by the two cycles of exposure to DSS is reduced by treatment with DABS. Treatment with DABS beneficially affects the clinical evolution of IBD, as demonstrated by the determination of the clinical score of the disease (Figure 2) that is reduced due to the administration i.p. and oral DABS in the first two cycles of DSS. In addition, it is shown that the efficacy of DABS is not less (in some places it is greater) than that corresponding to the standard treatment with Solu-Medrol (Figures 1 and 2).

Example 7: Inhibition of fibroblast mitogenesis induced by fibroblast growth factor 1 (FGF-1).

Inhibition of FGF-1-induced mitogenesis was observed in quiescent cultures of Balb / c 3T3 fibroblasts by 2-acetoxy-5-hydroxybenzenesulfonate (Figure 3), 5-acetoxy-2-hydroxybenzenesulfonate (Figure 4) and 2,5diacetoxybenzenesulfonate (figure 5). The compounds evaluated in the form of potassium salt were used, except in the first case in which calcium salt was used. Experiments were carried out as described in Fernández-Tornero C. et al. J. Biol. Chem., 2003.

Example 8: Analysis of the structural interaction of 2,5-dihydroxybenzenesulfonate esters with fibroblast growth factor 1 (FGF-1).

Based on the crystalline diffraction of FGF-1 complexes: 2-acetoxy-5-hydroxybenzenesulfonic acid, FGF-1: 5-acetoxy-2-hydroxybenzenesulfonic acid and FGF-1: 2,5-diacetoxybenzenesulfonic acid, the structures of

the complexes and were represented. Figures 6, 7 and 8, which show the surface of the stained protein according to its electrostatic potential (light gray: negative charge, dark gray: positive charge, white: lack of charge), show the way in which 2-acetoxy acid interact -5-hydroxybenzenesulfonic acid, 5-acetoxy-2-hydroxybenzenesulfonic acid and 2,5-diacetoxybenzenesulfonic acid, respectively, with FGF-1. The electron density of the compound, with 5 contours at 1 (Figures 6-8, panels C), allowed to locate and determine the orientations of the compounds with respect to the protein (Figures 6-8, panels A and B), as well as confirm that the compounds retain the acetoxyl groups at positions 2, 5 and 2 and 5, respectively, when they bind to the protein. The compounds occupy a place that is very close to what has been described as occupied by 2,5-dihydroxybenzenesulfonic acid, whose aromatic ring forms a cation- bond with the N grupo group of lysine 132, which is marked in Figures 6 -8, panels A,

10 as a reference.

Claims (8)

one.

Use of a compound selected from the group consisting of: 2- (acetyloxy) -5-hydroxybenzenesulfonic acid; 5- (acetyloxy) -2-hydroxybenzenesulfonic acid; 2,5-bis (acetyloxy) benzenesulfonic acid; 2- (acetyloxy) -5-hydroxybenzenehomosulfonic acid; 5- (acetyloxy) -2-hydroxybenzenehomosulfonic acid; 2,5-bis (acetyloxy) benzene sulfosulfonic acid;

and pharmaceutically acceptable salts thereof, in the manufacture of a medicament for the treatment and / or prophylaxis of a disease selected from arthritis and pain

2.

Use according to claim 1, wherein the compound is selected from: 2- (acetyloxy) -5hydroxybenzenesulfonic acid; 5- (acetyloxy) -2-hydroxybenzenesulfonic acid and 2,5bis (acetyloxy) benzenesulfonic acid.

3.

Use according to any of the preceding claims, wherein the arthritis is selected from osteoarthritis, rheumatoid arthritis, polyarthritis, gouty arthritis, lupus-related arthritis, psoriasis-related arthritis, infectious arthritis, including viral, parasitic and bacterial arthritis.

Four.

Use according to any of the preceding claims, wherein the medicament is administered topically, transdermally, orally, orally, parenterally, by inhalation, rectal, intravaginal, intraocular, otic or intraarticular.

5.

Use according to any of the preceding claims wherein the medicament comprises at least one additional therapeutic agent.

6.

Use according to claim 5, wherein at least one additional therapeutic agent is selected from the group consisting of a chemotherapeutic agent, a corticosteroid, an antibiotic, an analgesic, an alpha-adrenergic blocker, a beta-adrenergic agonist, an anticholinergic, a 5-alpha-reductase inhibitor, an antiandrogen, an immunomodulator, an immunosuppressant, an antiangiogenic such as anti-VEGF, anti-FGF, anti-HGF and anti-EFG, a leukotriene modifier, an aminosalicylate, an anesthetic, an anti-inflammatory non-steroidal, an antiparasitic, a solubilized interleukin receptor therapy, intramuscular gold, a cytotoxic, an antioxidant and combinations of two or more thereof.

7.

A compound selected from the group consisting of: 2- (acetyloxy) -5-hydroxybenzenesulfonic acid; 5- (acetyloxy) -2-hydroxybenzenesulfonic acid; 2,5-bis (acetyloxy) benzenesulfonic acid; 2- (acetyloxy) -5-hydroxybenzenehomosulfonic acid; 5- (acetyloxy) -2-hydroxybenzenehomosulfonic acid; 2,5-bis (acetyloxy) benzene sulfosulfonic acid;

and pharmaceutically acceptable salts thereof, for use in the treatment and / or prophylaxis of any of the diseases selected from the group that It consists of arthritis and pain.

8.

Compound according to claim 7, which is selected from: 2- (acetyloxy) -5-hydroxybenzenesulfonic acid; 5- (acetyloxy) -2-hydroxybenzenesulfonic acid and 2,5-bis (acetyloxy) benzenesulfonic acid.