(19) & (11) EP 2 494 967 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 05.09.2012 Bulletin 2012/36 A61K 31/155 (2006.01) A61K 31/60 (2006.01) A61K 45/06 (2006.01) A61K 31/4045 (2006.01) (21) Application number: 12170283.1 (22) Date of filing: 16.01.2008 (84) Designated Contracting States: (72) Inventor: Chen, Chien-Hung AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Forest Hills, NY New York 11375 (US) HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT RO SE SI SK TR (74) Representative: Coehn, Markus Fish & Richardson P.C. (30) Priority: 16.01.2007 US 885212 P Mies-van-der-Rohe-Strasse 8 80807 München (DE) (62) Document number(s) of the earlier application(s) in accordance with Art. 76 EPC: Remarks: 08727718.2 / 2 118 279 This application was filed on 31-05-2012 as a divisional application to the application mentioned (71) Applicant: IPINTL, LLC under INID code 62. Flushing, NY 11354 (US) (54) Novel composition for treating metabolic syndrome (57) The invention relates to a composition that in- kinase (AMPK) activator; a second agent that possesses cludes a first agent selected from the group consisting anti-inflammatory activity; and a third agent that possess- of an oxidative phosphorylation inhibitor, an ionophore, es serotonin activity. and an adenosine 5’-monophosphate-activated Protein EP 2 494 967 A1 Printed by Jouve, 75001 PARIS (FR) 1 EP 2 494 967 A1 2 Description serotonin (e.g., serotonin sulfate, a serotonin creatinine sulfate complex, or serotonin hydrochloride) and a sero- CROSS-REFERENCE TO RELATED APPLICATION tonin re-uptake inhibitor. A preferred composition con- tains metformin hydrochloride, aspirin, and a serotonin [0001] This application claims the benefit of US Provi- 5 creatinine sulfate complex. The three agents mentioned sional Application 60/885,212, filed January 16, 2007, above can treat the target diseases via biological mech- the content of which is incorporated herein by reference anisms other than those described therein. For example, in its entirety. metformin may treat a target disease (e.g., diabetes) via a mechanism other than inhibiting oxidative phosphor- BACKGROUND 10 ylation or activating AMPK. [0005] In another aspect, the invention features a com- [0002] Metabolic syndrome is characterized by a position consisting essentially of a first agent that can be group of metabolic risk factors, including abdominal an oxidative phosphorylation inhibitor, an ionophore, or obesity, atherogenic dyslipidemia (e.g., high triglyceride an AMPK activator, a second agent that possesses anti- levels, low HDL cholesterol levels, and high LDL choles- 15 inflammatory activity, and a third agent that possesses terol levels), hypertension, insulin resistance, prothrom- serotonin activity. The term "consisting essentially of" botic state (e.g., high fibrinogen or plasminogen activator used herein limits a composition to the three specified inhibitor-1 levels), and proinflammatory state (e.g., ele- agents and those that do not materially affect its basic vated C-reactive protein levels). Metabolic syndrome has and novel characteristics, i.e., the efficacy in treating a become increasingly common in the United States. It is 20 target disease described herein. An example of such a estimated that over 50 million Americans have this dis- composition contains the above- mentioned three agents order. There is a need to develop novel drugs to effec- and a pharmaceutically acceptable carrier. tively treat this disorder. [0006] The compositions described above can contain 5-5,000 mg (e.g., 5-3,000 mg, 5-1,500 mg or 5-1,000 mg) SUMMARY 25 of the first agent, 1-5,000 mg (e.g., 1-3000 mg, 1-1,000 mg, 1-500 mg, or 1-100 mg) of the second agent, and [0003] This invention is based on the unexpected dis- 0.1-1,000 mg (e.g., 0.1-100 mg, 0.1-50 mg, or 0.1-30 mg) covery that a combination of certain known drugs exhibits of the third agent, or in quantities of the same ratio as synergistic effects in treating metabolic syndrome and that calculated based on the above amounts. various other diseases. 30 [0007] In still another aspect, this invention features a [0004] In one aspect, the invention features a compo- method for treating metabolic syndrome, Parkinson’s dis- sition that includes a first agent that can be an oxidative ease, or polycystic ovarian syndrome. The method in- phosphorylation inhibitor, an ionophore, or an adenosine cludes administering to a subj ect in need thereof an ef- 5’-monophosphate-activated Protein kinase (AMPK) ac- fective amount of one or more of the compositions de- tivator, a second agent that possesses anti- inflammatory 35 scribed above. The diseases mentioned above also in- activity, and a third agent that possesses or maintains clude their associated disorders. For example, disorders serotonin activity. The term "oxidative phosphorylation associated with metabolic syndrome include atheroscle- inhibitor" refers to any suitable agents that inhibit oxida- rosis, coronary heart disease, stroke, obesity, diabetes, tive phosphorylation, such as oxidative phosphorylation atherogenic dyslipidemia (e.g., high triglyceride levels, uncouplers. An ionophore is a lipid- soluble molecule ca- 40 low HDL cholesterol levels, and high LDL cholesterol lev- pable of transporting an ion across the lipid bilayer of cell els), hypertension, insulin resistance, prothrombotic membranes; and an AMPK activator is an agent that ac- state (e.g., high fibrinogen or plasminogen activator in- tivates AMPK to phosphorylate its substrates, e.g., hibitor-1 levels), and proinflammatory state (e.g., elevat- acetyl-CoA carboxylase and malonyl-CoA decarboxyla- ed C-reactive protein levels). se. Examples of the first agent include metformin (e.g., 45 [0008] The term "treating" or "treatment" used herein metformin chloride), phenformin, buformin, ephedrine, refers to administering one or more above-described thyroxine, salicylanilide, and salicylic acid. The second compositions to a subject, who has a disease described agent can be any suitable anti- inflammatory compounds above, a symptom of such a disease, or a predisposition (e.g., non-steroidal anti-inflammatory compounds). Ex- toward such a disease, with the purpose to confer a ther- amples include aspirin, diclofenac (e.g., diclofenac po- 50 apeutic effect, e.g., to cure, relieve, alter, affect, amelio- tassium or diclofenac sodium), ibuprofen (e.g., dexibu- rate, or prevent the disease, the symptom of it, or the profen or dexibuprofen lysine), indomethacin, acetami- predisposition toward it. nophen, nimesulide, and a COX-2 inhibitor (e.g., a nitric [0009] The composition described above can be in dry oxide-based COX-2 inhibitor). The third agent can be a form (e.g., powder or tablet) or in aqueous form (e.g., compound possessing or maintaining at least one of the 55 beverage or syrup). It can be a dietary supplement or a serotonin’s activities and, when used in combination with pharmaceutical formulation (containing a pharmaceuti- the first and second agents, effectively treats one or more cally acceptable carrier). It can also be a drink or a food the target diseases of this invention. Examples includes product. Examples include tea (e.g., a tea drink and the 2 3 EP 2 494 967 A1 4 contents of a tea bag), soft drinks, juice (e.g., a fruit ex- 2,4-bis(p-chloroanilino)pyrimidine, glyceraldehyde-3- tract and a juice drink), milk, coffee, cookies, cereals, phosphate dehydrogenase, oligomycin, tributyltin chlo- chocolates, and snack bars. ride, aurovertin, rutamycin, venturicidin, mercurials, di- [0010] The first, second, and third agents described cyclohexylcarbdiimide, Dio-9, m-chlorophenyl-hydrazo- above include active compounds, as well as their salts, 5 ne mesoxalonitrile, ionomycin, calcium ionophores (e.g., prodrugs, and solvates, if applicable. A salt, for example, A23187, NMDA, CA 1001, or enniatin B), compounds can be formed between an anion and a positivelycharged that increase the Ca+2 concentration in mitochondria group (e.g., amino) on an agent. Suitable anions include (e.g., atractyloside, bongkrekic acid, thapsigargin, amino chloride, bromide, iodide, sulfate, nitrate, phosphate, ci- acid neurotransmitters, glutamate, N-methyl-D-aspartic trate, methanesulfonate, trifluoroacetate, acetate, chlo- 10 acid, carbachol, ionophores, inducers of potassium de- rophenyoxyacetate, malate, tosylate, tartrate, fumarate, polarization), apoptogens (i.e., compounds that induce glutamate, glucuronate, lactate, glutarate, benzoate, em- apoptosis), valinomycin, gramicidin, nonactin, nigericin, bonate, glycolate, pamoate, aspartate, parachlorophe- lasalocid, and monensin. The first agent can be an AMPK noxyisobutyrate, formate, succinate, cyclohexanecar- activator (e.g., metfomin or phenformin, buformin, AIC- boxylate, hexanoate, octonoate, decanoate, hexade-15 AR, thienopyridones, resveratrol, nootkatone, thiazole, canoate, octodecanoate, benzenesulphonate, trimeth- or adiponectin) oxybenzoate, paratoluenesulphonate, adamantanecar- [0015] The second agent can include steroidal anti- boxylate, glycoxylate, pyrrolidonecarboxylate, naphtha- inflammatory drugs and non-steroidal anti-inflammatory lenesulphonate, 1-glucosephosphate, sulphite, dithion- drugs. Examples of steroidal anti- inflammatory drugs in- ate, and maleate. Likewise, a salt can also be formed 20 clude glucocorticoids, hydrocortisone, cortisone, beclo- between a cation and a negatively charged group (e.g., methasone, dipropionate, betamethasone, dexametha- carboxylate) on an agent. Suitable cations