NEW POLYMETHOXYFLAVONOID COMPOUNDS SUBSTITUTED AT POSITION 5, PROCESSES FOR THEIR PREPARATION AND COMPOSITIONS CONTAINING THEM

Abstract

NEW POLYMETHOXYFLAVONOID COMPOUNDS SUBSTITUTED AT POSITION 5, PROCESSES FOR THEIR PREPARATION AND COMPOSITIONS CONTAINING THEM. Compounds of formula (I): R represents a hydrogen or halogen atom or a hydroxy, methoxy, alkoxy, acyloxy, alkyl, or aryl group. Processes for their preparation and compositions containing them for therapeutic, cosmetic, and food applications.

Description

Title of the invention: NEW POLYMETHOXYFLAVONOID COMPOUNDS SUBSTITUTED AT POSITION 5, METHODS FOR THEIR PREPARATION AND COMPOSITIONS CONTAINING THEM

[0001] The present invention relates to novel 5-substituted polymethoxyflavonoid compounds, processes for their preparation, and compositions containing them. This invention is useful for the preparation of pharmaceuticals, cosmetics, and food products.

[0002] More than 6,000 natural flavonoids have been characterized from various plants. Flavones and flavonols are two subclasses of flavonoids. Diosmetin, luteolin, and apigenin derivatives are examples of flavones. Quercetin and kaempferol derivatives are examples of flavonols. Flavonoids are often glycosylated in nature. Flavones are generally glycosylated at the 7-position. Diosmin is an example of a 7-O-glycosylated flavone; 7-O-[3-rutinosyl diosmetin.] Flavonols are generally glycosylated at the 3- or 7-position. Examples of 3-O-glycosylated flavonols include rutin and 3-O-[3-rutinosyl quercetin.]

[0003] Polymethoxyflavonoids constitute a particular class of flavonoids. The difference between polymethoxyflavonoids and other flavonoids is that the former possess more than one methoxy group, which appears to significantly influence the bioactivities of polymethoxyflavonoids. Polymethoxyflavonoids are less abundant than flavonoids or glycosylated flavonoids in nature. Examples of polymethoxyflavonoids include nobiletin and tangeretin, as well as their metabolites, 5-desmethylnobiletin and 5-desmethyltangeretin.

[0004] Very few 5-O-glycosylated polymethoxyflavonoids have been identified in plant extracts. For example, 5-glucosyl gardenin A was described in the publication Nat. Acad. Sci. Letters 1988 vol. 11, No. 9, 281, 5-glucosyl gardenin B was described in the publication Chem. Biodiversity 2016, 13, 1641, lethedoside was described in the publication J. Nat. Prod. 1999, 62(2) 241, 5-glucosyl tectochrysine was described in the publication Phytochemistry 1990, 29(4) 1351, 5-glucosyl salvigenine was described in the publication Lloydia 1975, 38(5) 446 and 5-glucosyl-7,4'-dimethylapigenin was described in the publication Youji Huaxue 2019, 39(2) 561. A 5-acetoxy-6,7,8,3',4'-pentamethoxyflavone was described in the publications J. Agric. Food Chem. 2016, 64, 3196 and Immunopharmacol Immunotoxicol 2024 Jun4;1-11.

[0005] Polymethoxyflavonoids such as nobiletin have a broad spectrum of biological properties described in the publications Int. J. of Food Properties 2023, vol.26, No.1, 866 and Phytomedicine 2022 Sep; 104:154285.

[0006] Polymethoxyflavonoids and flavonoids in general activate antioxidant pathways that have an anti-inflammatory effect. Flavonoids as potential anti-inflammatory molecules were reviewed in Molecules 2022, 27, 2901. They modulate the expression and activation of cytokines such as interleukin-6 (IL-6) and monocyte chemotactic protein-1 (MCP-1). Inflammation is a common denominator in several age-related pathologies. Chronic systemic inflammation is closely linked to cardiovascular disease, obesity, type 2 diabetes, cancer, and neurodegenerative diseases. The importance of inflammation in most diseases is well documented, and a recent example was described in the publication entitled "The superpower of GLP-1 agonist obesity drugs: taming inflammation" in Nature 626, 246 (2024).

[0007] As the largest organ, the skin provides immunological protection and maintains physical integrity from the external environment. The skin protects against exposure to UV light, pollutants, and allergens, which are sources of oxidative stress and DNA damage. These aggressors promote and develop a variety of skin diseases such as psoriasis, vitiligo, photodamage, skin cancer, and atopic dermatitis. These aggressors are also responsible for altering the skin's homogeneity, causing sagging, wrinkles, roughness, and dryness.

[0008] Nobiletin has been described to reduce skin inflammation in the publications J. Agric. Food Chem 2018 Aug8; 66(31):8299 and Cancer Res. 2000 Sepl5;60(18):5059. It is described as a novel sun reagent potentially useful for application for skin protection against photoinflammation and photoaging in the publication Biochem. Pharmacol. 2004 Augl; 68(3):433. Examples of skin benefits of flavonoids and polymethoxyflavonoids have been described in the publications Int. J. Mol. Sci. 2023, 24, 6324 and Biomedicine & Pharmacotherapy 2022, 145, 112461.

[0009] Examples of the broad spectrum of biological properties of nobiletin and 5-desmethylnobiletin have been described in the following patents: Shanghai Huajn Biotechnology Co. patent CN107510693 as a dipeptidyl peptidase IV inhibitor, Macau University of Science and Technology patent CN113398115 as a treatment for pigmented skin diseases, Huanggang Normal University patent WO2018125950 as an anticancer agent, KR1020170000068 as a skin hydration and wrinkle prevention agent, and JP2023072735. Juntendo for the treatment and prevention of xeroderma, patent JP2001240539 from Mashida & Mashida Shokai; as a drug or functional food for controlling elevated blood pressure or blood glucose, patent JP2000080035 from the National Institute of Fruit Tree Science as an inhibitor of matrix metalloproteinase production. Nobiletin and "Chenpi"—dried citrus peel rich in nobiletin used in traditional Chinese medicine to treat numerous diseases—are currently undergoing clinical evaluation for body fat reduction in Taiwan (clinical trial NCT04910646) and for non-alcoholic fatty liver disease (NAFLD) in Japan (clinical trial jRCTs051180071).

[0010] Although flavonoids, polymethoxyflavonoids, and nobiletin have demonstrated numerous health benefits, their low water solubility and bioavailability limit their in vivo bioactivity and are a cause for concern. Improving water solubility and bioavailability would therefore be of paramount importance in order to exert optimal health benefits in vivo. These limitations are even more significant for nobiletin and polymethoxyflavonoids due to their more hydrophobic nature resulting from the multiple methoxy groups on the polymethoxyflavonoid structures. In this regard, numerous attempts have been made to increase the bioavailability of flavonoids and polymethoxyflavonoids through sophisticated formulations.An overview of advanced formulation and nanotechnology-based strategies for nobiletin was described in AAPS PharmSciTech (2020) 21:226. To improve nobiletin delivery, a transdermal formulation using ionic liquids was described in Sci.Rep. (2019) 9;20191. Methods for producing a solubilized nobiletin composition were described in Karii Life:KK patent JP2008074723, and methods for producing a solid dispersion containing nobiletin were described in Kao Corp patent JP2019167336 and Guangzhou Medical University patent CN116077441.

[0011] The applicant has now discovered that certain novel 5-O-substituted polymethoxyflavonoids have first of all a surprisingly good solubility in water, which allows for easier, simpler and safer formulations to improve their administration and efficacy, and also have very good anti-inflammatory activity.

[0012] More specifically, the present invention relates to novel 5-substituted polymethoxyflavonoid compounds of formula (I):

[0013] R represents a hydrogen or halogen atom or a hydroxy, methoxy, alkoxy, acyloxy, alkyl or aryl group.

[0014] The O-glycoside fraction of the sugar:

[0015] is a glucosyl, mannosyl or galactosyl group, depending on its stereochemistry:

[0016] The compound of formula (I) may be 5-O-beta-substituted or 5-O-alpha-substituted:

[0017] The present invention also relates to methods for preparing compounds of formula (I) from a compound of formula (II): (II)

[0018] The O-glycosylated compounds were prepared using microorganisms according to the procedures described in the publications Polish Journal of Microbiology 2016, Vol.65, No2, 137-151 and Int. J. Mol. Sci. 2020, 21, 6121 or using the Koenigs knorr reaction conditions with glycosylated bromide according to the procedure described in the publication Front. Chem. 2021; 9:637994.

[0019] The compounds of formula (II) were prepared from the compounds of formula (III) according to the procedure described in the publications Org. Process Res. Dev. 2019, 23, 595 or LWTFood Science and Technology 2019, 116, 108469. (III)

[0020] Compounds of formula (III) in which R is not a hydrogen have been prepared from 3-bromonobiletin according to the Suzuki reaction procedures described in the publication Tetrahedron 62 (2006) 4038. 3-Bromonobiletin was prepared from nobiletin using N-bromosuccinimide as described in the publication Tetrahedron 62 (2006) 4038.

[0021] The compounds of the invention are anti-inflammatory agents. They modulate the expression and activation of cytokines such as interleukin-6 (IL-6) and monocyte chemotactic protein-1 (MCP-1). They are therefore useful in the prevention or treatment of cardiovascular diseases, obesity, type 2 diabetes, cancer, neurodegenerative diseases, age-related diseases, and skin diseases such as psoriasis, vitiligo, photodamage of the skin, skin cancer, and atopic dermatitis. They are also useful for preserving the radiance and evenness of the skin and for preventing sagging, wrinkles, roughness, and dryness.

[0022] The present invention also relates to compositions comprising as an active ingredient a compound of formula (I), in combination with one or more pharmaceutically acceptable, non-toxic and inert carriers or excipients. Among the compositions according to the invention, particular mention may be made of those suitable for oral, parenteral (intravenous, intramuscular or subcutaneous), percutaneous or transcutaneous, nasal, rectal, sublingual, ocular or respiratory administration, and in particular tablets or sublingual tablets, hard gelatin capsules, softgels, suppositories, creams, ointments, dermal gels, injectable or oral preparations, aerosols, eye drops and nasal drops.

[0023] The following examples illustrate the present invention. The structures of the compounds described in the examples were determined using conventional spectrophotometric techniques (nuclear magnetic resonance, mass spectrometry). ABBREVIATIONS

[0024] DCM Dichloromethane

[0025] Dexa Dexamethasone

[0026] DMF Dimethylformamide

[0027] DMSO Dimethyl sulfoxide

[0028] EtOH Ethanol

[0029] IL-6 Interleukin-6

[0030] LC-MS Liquid Chromatography-Mass Spectrometry

[0031] LPS Lipopolysaccharide

[0032] NBS N-bromosuccinimide

[0033] NMR Nuclear Magnetic Resonance

[0034] MCP-1 Monocyte Chemoattractant Protein-1

[0035]

[0036]

[0037]

[0038] MeOH Methanol MgSO4 Magnesium sulfate UDCA Ursodeoxycholic acid EXAMPLE 1: 5-OpD-glucosyl-5-desmethylnobiletin

[0039] Procedure A; Biotransformation with microorganisms

[0040] Erlenmeyer flasks (250 mL), each containing 100 mL of sterile culture medium (3% glucose, 1% peptone), were inoculated with a suspension of each strain and then incubated for 3 days at 24°C on a rotary shaker. After this period, 5-desmethylnobiletin CAS 2174-59-6 (50 mg) was dissolved in dimethyl sulfoxide (DMSO) (2 mL) and added. Samples were taken on days 1, 3, 7, and 10 of the process. Subsequently, all products were extracted using methanol, and the extracts were dried over MgSO4, concentrated under vacuum, and analyzed using LC-MS methods.

[0041] The following strains: Beauveria Bassiana ATTC 74040, Rhizopus Nigricans NRRL 1477 and Aspergilus Niger BO transformed 5-demethylnobiletin into 5-O-[3-D-glucosyl-5-demethylnobiletin with a conversion rate of 56%, 96% and 0% respectively. Procedure B; Summary

[0042] Step 1: [(2R,3R,4S,5R,65)-3,4,5-Triacetoxy-6-[2-(3,4-dimethoxyphenyl)-6,7,8-trimethoxy-4-oxo-chromen-5-yl]oxy-tetrahydropyran-2-yl]methyl acetate

[0043] To a solution of 5-desmethylnobiletin CAS 2174-59-6 (2.0 g, 5.15 mmol) in toluene (40 mL), Cs₂CO₃ (5.03 g, 15.5 mmol) was added. The mixture was stirred for 10 minutes, and then acetobromo-α-D-glucose (6.35 g, 15.5 mmol) was introduced. The reaction was heated at 65 °C for 18 hours. After cooling to room temperature, the insoluble fraction was recovered by filtration. The resulting filtrate was evaporated to dryness and purified by silica chromatography with DCM / MeOH = 98 / 2 as the eluent to obtain [(2R,3R,4S,5R,65)-3,4,5- Triacetoxy-6-[2-(3,4-dimethoxyphenyl)-6,7,8-trimethoxy-4-oxo-chromen-5-yl]oxy-tetrahydropyran-2-yl] methyl acetate (2.86 g, 77% yield).

[0044] 'H NMR (400 MHz, DMSO-76): <5 7.65 (dd, 7=8.5 Hz, 2.1 Hz, 1H), 7.54 (d, J = 2.1 Hz, 1H), 7.17 (d, J= 8.7 Hz, 1H), 6.86 (s, 1H), 5.37 (d, J= 7.5 Hz, 1H), 5.33 (t, J = 9.3 Hz, 1H), 5.11 (dd, 7=9.3 Hz, 7.5 Hz, 1H), 5.01 (t,7=9.6 Hz, 1H), 4.12-3.93 (2m, 3H), 4.02 - 3.82 (5 s, 15H), 2.02 - 1.90 (4 s, 12H).

[0045] LC-MS (ESI): (m / z) [M+H]+ calculated for [C34H38O17]+719.66; found 719.16.

[0046] Step 2: 5-O-[3-D-glucosyl-5-desmethylnobiletin

[0047] To a solution of [(2,37,45,57,65)-3,4,5-Triacetoxy-6-[2-(3,4- methyl dimethoxyphenyl)-6,7,8-trimethoxy-4-oxo-chromen-5-yl]oxy-tetrahydropyran-2-yl]acetate (2.42 g, 3.37 mmol) in anhydrous DMF (32 mL) and EtOH (32 mL) was mixed with sodium ethoxide (21 wt% in ethanol) (0.251 mL, 0.673 mmol). The mixture was heated at 35 °C for 2 hours. Dowex 50 WX8 resin was added, and after filtration, the crude product was purified by silica chromatography with DCM / MeOH = 85 / 15 as the eluent to obtain 5-O-[3-D-glucosyl-5-desmethylnobiletin (1.10 g, 59% yield).

[0048] 'H NMR (400 MHz, DMSO-76): <5 8.03 (dd, 7 = 8.5 Hz, 2.2 Hz, 1H), 7.57 (d, 7 = 2.1 Hz, 1H), 7.18 (d, 7 = 8.7 Hz, 1H), 6.98 (s, 1H), 5.80 (d, 7 = 2.8 Hz, 1H), 5.05 (d, 7 = 5.0 Hz, 1H), 4.96 (d, 7 = 4.9 Hz, 1H), 4.76 (d, 7 = 7.8 Hz, 1H), 4.40 (t, 7 = 5.1 Hz, 1H), 4.07 - 3.83 (5 s, 15H), 3.74 - 3.66 (m, 1H), 3.50 - 3.42 (m, 1H), 3.40 - 3.33 (m, 1H), 3.27 - 3.08 (m, 3H).

[0049] LC-MS (ESI): (m / z) [M+H]+ calculated for [C26H30O13]+ 550.51; found 551.16.

[0050] EXAMPLE 2: 5-OpD-galactosyl-5-desmethylnobile tine OH

[0051] Procedure B of Example 1 was followed using 5-desmethylnobiletin cas 2174-59-6 (350 mg, 0.901 mmol) and acetobromo-α-D-galactose (1.11 g, 2.70 mmol) to obtain 5-O-[3-D-galactosyl-5-desmethylnobiletin (88 mg, 17% yield).

[0052] 'H NMR (400 MHz, DMSO-76): <5 7.69 (dd, J = 8.5 Hz, 2.2 Hz, 1H), 7.58 (d, J = 2.2 Hz, 1H), 7.00 (s, 1H), 7.19 (d, J = 8.8 Hz, 1H), 5.71 (d, J = 2.7 Hz, 1H), 4.91 (d, J = 5.8 Hz, 1H), 4.68 (d, 7 = 7.8 Hz, 1H), 4.55 (t, J = 5.6 Hz, 1H), 4.51 (d, J = 4.4 Hz, 1H), 4.05 - 3.99 (2 s, 6H), 3.90 - 3.81 (3s, 9H), 3.72 - 3.62 (m, 2H), 3.62 - 3.54 (m, 1H), 3.51 - 3.44 (m, 1H), 3.40 - 3.31 (m, 2H).

[0053] LC-MS (ESI): (m / z) [M+H]+ calculated for [C26H30O13]+ 551.51; found 551.17. EXAMPLE 3: 5-O-mannosyl-5-desmethylnobiletin

[0055] Procedure B of Example 1 was followed using 5-desmethylnobiletin cas 2174-59-6 (500 mg, 1.29 mmol) and racetobromo-αD-mannose (1.59 g, 3.86 mmol) to obtain 5-O-mannosyl-5-desmethylnobiletin (46 mg, 7% yield) as an a / P:82 / 18 anomer mixture.

[0056] Anomer a:

[0057] 'H NMR (400 MHz, DMSO-76): <5 7.66 (dd, J = 8.5 Hz, 2.2 Hz, 1H), 7.55 (d, J = 2.2 Hz, 1H), 7.17 (d, 7 = 8.7 Hz, 1H), 6.85 (s, 1H), 5.18 (d, 7= 1.6 Hz, 1H), 4.82 (d, 7 = 4.5 Hz, 1H), 4.75 (d, 7= 5.2 Hz, 1H), 4.62 (d, 7= 5.8 Hz, 1H), 4.27 - 4.23 (m, 1H), 4.15 (t, 7 = 6.1 Hz, 1H), 4.02 - 3.98 (2s, 6H), 3.95 - 3.84 (m, 7H), 3.84 - 3.77 (m, 4H), 3.62 - 3.55 (m, 1H), 3.53 - 3.48 (m, 2H).

[0058] Anomer P:

[0059] ‘H NMR (400 MHz, DMSO-76): <5 7.67 (dd, 7 = 8.6 Hz, 2.0 Hz, 1H), 7.56 (d, 7 = 2.2 Hz, 1H), 7.18 (d, 7= 8.8 Hz, 1H), 6.92 (s, 1H), 5.38 (d,7= 1.9 Hz, 1H), 5.29 (d, 7=0.6 Hz, 1H), 4.75 (d, 7 =5.2 Hz, 1H), 4.62 (d, 7= 5.8 Hz, 1H), 4.31 (t,7=5.5 Hz, 1H), 4.06 - 3.77 (m, 18H), 3.42 - 3.34 (m, 2H), 3.10 - 3.03 (m, 1H).

[0060] LC-MS (ESI): (m / z) [M+H]+ calculé pour [C26H30O13]+551.51; trouvé 551.14. EXAMPLE 4: 3-bromonobilétine

[0061]

[0062] N-Bromosuccinimide (4.4 g, 24.9 mmol) was added to a solution of nobiletin (5 g, 12.4 mmol) in DCM / Pyridine (520 / 105 mL). The reaction mixture was stirred at room temperature for 16 hours, treated with Na₂S₂O₃ aq (IM), and extracted three times with DCM. The organic phase was washed with water, dried over MgSO₄, filtered, concentrated to dryness, and purified by silica chromatography with petroleum ether / EtOAc = 1:1 as the eluent to obtain 3-bromonobiletin (2.5 g, 41% yield).

[0063] *H NMR (250 MHz, CDC13) ô 7.59 (dd, J = 8.4, 2.1 Hz, 1H), 7.50 (d, J = 2.1 Hz, 1H), 7.00 (d, J = 8.6 Hz, 1H), 4.10 (s, 3H), 3.98 (s, 3H), 3.97 (s, 3H), 3.95 (s, 3H), 3.95 (s, 3H), 3.94 (s, 3H). EXAMPLE 5: 3-bromo-5-desmethylnobiletin

[0065] A solution of BC13 in DCM (IM, 0.5 mL, 0.5 mmol) was added dropwise to a solution of 3-bromonobiletin (0.2 g, 0.42 mmol) in DCM (18 mL) at -78°C under Argon. The reaction mixture was stirred at -78°C for 20 min and then at room temperature for 16 h, neutralized with IM NaOH, and the pH was adjusted with 3M HCl. The aqueous phase was extracted twice with DCM, dried over MgSO4, filtered, concentrated, and purified by silica chromatography with DCM / MeOH 99 / 1 as the eluent to obtain 3-bromo-5-desmethylnobiletin (40 mg, 21% yield).

[0066] 1H NMR (400 MHz, CDC13) ô 12.18 (s, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.50 (s, 1H), 7.01 (d, J = 8.4 Hz, 1H), 4.12 (s, 3H), 3.98 (s, 3H), 3.96 (s, 6H), 3.91 (s, 3H).

[0067] EXAMPLE 6: 2,3-bis(3,4-dimethoxyphenyl)-5,6,7,8-tetramethoxy-chromene-4-one

[0068] To a solution of 3-bromonobiletin (300 mg, 0.62 mmol) in dioxane (18 mL), 3,4-dimethoxyphenylboronic acid (181 mg, 0.995 mmol), Pd(PPh3)4 (36 mg, 0.03 mmol), and a 2 M potassium carbonate solution (1 mL, 2 mmol) were added under argon. The reaction was heated under reflux for 16 h. The mixture was cooled, diluted with water and aqueous IM HCl to achieve a pH of 6, and extracted twice with DCM. The organic phase was washed with water, dried over MgSO4, filtered, concentrated to dryness and purified twice by silica chromatography, first with DCM / MeOH 99 / 1 to 98 / 2 and then with DCM / MeOH 100 / 0 to 98 / 2 as eluent to obtain 2,3-bis(3,4-dimethoxyphenyl)-5,6,7,8-tetramethoxy-chromene-4-one (245 mg, 73% yield).

[0069] ‘H NMR (400 MHz, DMSO) ô 7.12 (dd, J = 8.5, 2.1 Hz, 1H), 6.98 (d, J = 8.7 Hz, 1H), 6.92 (d, J = 8.3 Hz, 1H), 6.86 (d, J = 2.2 Hz, 1H), 6.81 (d, J = 2.0 Hz, 1H), 6.67 (dd, J = 8.2, 2.0 Hz, 1H), 4.04 (s, 3H), 3.95 (s, 3H), 3.85 (s, 3H), 3.80 - 3.72 (m, 9H), 3.64 (s, 3H), 3.47 (s, 3H).

[0070] EXEMPLE 7 : 2-(3,4-diméthoxyphényl)-5,6,7,8-tétraméthoxy-3-(3,4,5-triméthoxyphényl)chromen-4-one

[0071] To a solution of 3-bromonobiletin (300 mg, 0.62 mmol) in dioxane (18 mL), 3,4,5-trimethoxyphenylboronic acid (211 mg, 0.995 mmol), Pd(PPh3)4 (36 mg, 0.03 mmol), and a 2 M potassium carbonate solution (1 mL, 2 mmol) were added under argon. The reaction was heated under reflux for 16 h. The mixture was cooled, diluted with water and aqueous IM HCl to achieve a pH of 6, and extracted twice with DCM. The organic phase was washed with water, dried over MgSO4, filtered, concentrated to dryness and purified twice by silica chromatography first with DCM / MeOH 99 / 1 to 98 / 2 and then with Petroleum ether / EtOAc = 6 / 4 to 4 / 6 as eluent to obtain 2-(3,4-dimethoxyphenyl)-5,6,7,8-tetramethoxy-3-(3,4,5-trimethoxyphenyl)chromen-4-one (195 mg, 55% yield).

[0072] 'H NMR (400 MHz, DMSO) ô 7.21 (dd, J = 8.4, 2.2 Hz, 1H), 7.02 (d, J = 8.6 Hz, 1H), 6.87 (d, J = 2.2 Hz, 1H), 6.51 (s, 2H), 4.04 (s, 3H), 3.96 (s, 3H), 3.85 (s, 3H), 3.78 (s, 7H), 3.67 (s, 3H), 3.64 (s, 6H), 3.46 (s, 4H). EXAMPLE 8: Solubility Study

[0073] Solubility of flavones and polymethoxyflavones (mg / mL in water at 25°C pH7.4) Compounds Predictions ACD Labs Observations nobiletin 0.039 0.016 5-demethyl Inobiletin 0.28 0.032 Example compound 1 5-O-[3-D-glucosyl-5-demethylnobiletin 0.23 100 Example compound 2 5-O-[3-D-galactosyl-5-demethylnobiletin 0.23 4.6 Example compound 3 5-O-mannosyl-5-demethylnobiletin 0.23 167 Diosmetin 1.89 <0.01 7-O-[3-D-glucosyl-diosmetin 4.7 <0.01 7-O-[3-rutinosyl diosmetin (diosmin) 1.49 0.019

[0074] The results show that some of the compounds of the present invention are considerably more soluble than the reference compounds. EXAMPLE 9: Composition of the solution

[0075] Formulation for preparing a 1% solution with the compound of Example 1

[0076] Compound of example 1: 100 mg

[0077] Water qs 10 mL EXAMPLE 10: Anti-inflammatory activity

[0078] The compounds of the invention significantly decrease the expression of pro-inflammatory cytokines such as interleukin-6 (IL-6) and monocytic chemotactic protein-1 (MCP-1) in the human monocytic leukemia cell line (THP-1).

[0079] The THP-1 cell line was incubated with compounds of formula (I) at IpM for Ih and then stimulated with Lipopolysaccharide (LPS) (100 ng / mL). Cytokines were quantified by ELISA methods after 24 h. The compound of Example 1 at IpM decreased IL-6 levels by 46% and MCP-1 levels by 59%, while 30 pM of UDCA decreased IL-6 levels by 38% and MCP-1 levels by 26%, and 1 nM of dexamethasone decreased IL-6 levels by 83% and MCP-1 levels by 59%.

Claims

Demands

1. Compound of formula (I):

2.

3. R represents a hydrogen or halogen atom or a hydroxy, methoxy, alkoxy, acyloxy, alkyl or aryl group. Compound of formula (I) according to claim 1, selected from; 5-O-[3-D-glucosyl-5-desmethylnobiletin, 5-O-[3-D-galactosyl-5-desmethylnobiletin, 5-O-mannosyl-5-desmethylnobiletin, 3-bromonobiletin, 3-bromo-5-desmethylnobiletin, 2,3-bis(3,4-dimethoxyphenyl)-5,6,7,8-tetramethoxy-chromen-4-one, 2-(3,4-dimethoxyphenyl)-5,6,7,8-tetramethoxy-3-(3,4,5- (trimethoxyphenyl)chromen-4-one, Methods for synthesizing a compound of formula (I) according to claim 1, from a compound of formula (II): (II) R represents a hydrogen or halogen atom or a hydroxy, methoxy, alkoxy, acyloxy, alkyl or aryl group.

4. Formulation composition comprising as active ingredient a compound of formula (I) according to claim 1 or claim 2, in combination with one or more pharmaceutically acceptable, non-toxic, inert carriers or excipients, selected from a liquid, solution, suspension, emulsion, syrup, mouthwash, drop, tablet, granule, powder, lozenge, capsule, caplet, pill, ampoule, bolus, suppository, tincture, gel, paste, ointment, cream, lotion, oil, foam, spray and aerosol.

5. Compound of claim 1, claim 2 or composition of claim 4 for use as a cosmetic product.

6. Compound of claim 1, of claim 2 or composition of claim 4 for use as a medicinal product.

7. Compound of claim 1, of claim 2 or composition of claim 4 for use as a food or beverage product.