HYDR0XYCH0LEST-5-ENE GLYCOSIDES AS INHIBITORS OF SGLT2

BACKGROUND

[0001] The present disclosure generally relates to compositions and methods for improving metabolic health. Specifically, the present disclosure relates to using a hydroxycholest- 5-ene glycoside or its derivatives as a sodium-glucose cotransporter-2 (SGLT2) inhibitor for improving metabolic health. For example, it was found for the first time that a hydroxycholest-5- ene glycoside or its derivatives can be used both as a food or supplement and as a sodium-glucose cotransporter-2 (SGLT2) inhibitor to effectively inhibit SGLT2, thus improving metabolic health.

[0002] The SGLT family proteins SGLT1 and SGLT2 play an important role in the maintenance of blood glucose homeostasis. SGLT2 is primarily expressed in the kidney in epithelial cells lining the first segment of the proximal convoluted tubule and promotes reabsorption of glucose from the glomerular filtrate back into the circulation. SGLT2 is responsible for approximately 90% of glucose reabsorption from the urine. By inhibiting SGLT2, an ideal inhibitor would prevent the reuptake of glucose from the glomerular filtrate in the kidney and subsequently lower the glucose level in the blood and promote the excretion of glucose in the urine.

[0003] SGLT1 is expressed in the gut epithelial lining and contributes to post-prandial glucose uptake into the blood. Inhibition of SGLT1 is associated with negative gastrointestinal side effects such as diarrhea. Phlorizin is a known natural compound inhibiting both SGLT1 and SGLT2. Phlorizin administration is associated with negative gastrointestinal effects. Phlorizin is not approved as a drug and cannot be added to food or supplement. Achieving specific or selective SGLT2 inhibition, or renal-specific pan SGLT inhibition is desirable and advantageous by avoiding potential negative gastrointestinal side effects.

[0004] The known SGLT2 inhibitors are an insulin-independent class of oral antihyperglycemic medication that clinicians use in the treatment of type 2 diabetes. There are four SGLT2 inhibitors approved by the Food and Drug Administration since 2013 : canagliflozin, dapagliflozin, empagliflozin and ertugliflozin.

[0005] The known SGLT2 inhibitors are a class of prescription medicines that are FDA-approved for use with diet and exercise to lower blood sugar in adults with type 2 diabetes. Medicines in the SGLT2 inhibitor class include canagliflozin, dapagliflozin, and empagliflozin. They are available as single-ingredient products and also in combination with other diabetes medicines such as metformin. SGLT2 inhibitors lower blood sugar by causing the kidneys to remove sugar from the body through the urine. However, none of these known SGLT2 inhibitors are natural compounds and they can only be use as a drug and not as a food or supplements.

[0006] There is a clear unmet need for new compounds and compositions as SGLT2 inhibitors for improving metabolic health. Needed in the art are new compounds and compositions as SGLT2 inhibitors, which can be used as a food or supplement for improving metabolic health.

SUMMARY

[0007] The present disclosure includes the recognition that administering a subject a compound of a hydroxycholest-5-ene glycoside or its derivatives or related compositions as a sodium-glucose cotransporter-2 (SGLT2) inhibitor can effectively inhibit SGLT2, thus improving metabolic health. Indeed, the compound of the hydroxycholest-5-ene glycoside or its derivatives or related compositions can be used as a food or supplement to a subject to effectively inhibit SGLT2, thus improving metabolic health.

BRIEF DESCRIPTION OF DRAWINGS

[0008] FIG. 1 is a graph showing normalized SGLT1 and SGLT2 inhibition activities of Compound 1.

[0009] FIG. 2 is a graph showing normalized SGLT1 and SGLT2 inhibition activities of Compound 2.

[0010] FIG. 3 is a graph showing normalized SGLT1 and SGLT2 inhibition activities of Compound 3.

[0011] FIG. 4 is a graph showing normalized SGLT1 and SGLT2 inhibition activities of Compound 4.

DETAILED DESCRIPTION

[0012] Definitions

[0013] Some definitions are provided hereafter. Nevertheless, definitions may be located in the “Embodiments” section below, and the above header “Definitions” does not mean that such disclosures in the “Embodiments” section are not definitions.

[0014] All percentages expressed herein are by weight of the total weight of the composition unless expressed otherwise. As used herein, “about,” “approximately” and “substantially” are understood to refer to numbers in a range of numerals, for example the range of -10% to +10% of the referenced number, preferably -5% to +5% of the referenced number, more preferably -1% to +1% of the referenced number, most preferably -0.1% to +0.1% of the referenced number. All numerical ranges herein should be understood to include all integers, whole or fractions, within the range. Moreover, these numerical ranges should be construed as providing support for a claim directed to any number or subset of numbers in that range. For example, a disclosure of from 1 to 10 should be construed as supporting a range of from 1 to 8, from 3 to 7, from 1 to 9, from 3.6 to 4.6, from 3.5 to 9.9, and so forth.

[0015] As used in this disclosure and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a component” or “the component” includes two or more components.

[0016] The words “comprise,” “comprises” and “comprising” are to be interpreted inclusively rather than exclusively. Likewise, the terms “include,” “including” and “or” should all be construed to be inclusive, unless such a construction is clearly prohibited from the context. Nevertheless, the compositions disclosed herein may lack any element that is not specifically disclosed herein. Thus, a disclosure of an embodiment using the term “comprising” includes a disclosure of embodiments “consisting essentially of’ and “consisting of’ the components identified.

[0017] The term “and/or” used in the context of “X and/or Y” should be interpreted as “X,” or “Y,” or “X and Y.” Similarly, “at least one of X or Y” should be interpreted as “X,” or “Y,” or “X and Y.” For example, “at least one dithionite or a functionally similar reducing agent” should be interpreted as “dithionite,” or “a functionally similar reducing agent,” or “both dithionite and a functionally similar reducing agent.”

[0018] Where used herein, the terms “example” and “such as,” particularly when followed by a listing of terms, are merely exemplary and illustrative and should not be deemed to be exclusive or comprehensive. As used herein, a condition “associated with” or “linked with” another condition, means the conditions occur concurrently, preferably means that the conditions are caused by the same underlying condition, and most preferably means that one of the identified conditions is caused by the other identified condition.

[0019] The term “Compound 1,” or “Alloside B,” as used herein, refers to (2R,3R,4S,5R,6R)-2-{[(lR,2S,3aS,3bS,7R,9R,9aR,9bS,l laS)-7-hydroxy-l-[(2S,3S)-3-hydroxy- 6-methylheptan-2-yl]-9a,l la-dimethyl-9-{[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6- (hy droxymethyl)oxan-2-yl] oxy } - lH,2H,3H,3aH,3bH,4H,6H,7H,8H,9H,9aH,9bH,10H,HH,l laH-cyclopenta[a]phenanthren-2- yl]oxy]-6-(hydroxymethyl)oxane-3,4,5-triol, with CAS number of 142735-55-5. It is also called (-)-Alloside B or P-D-Galactopyranoside, (ip,3p,16p,22S)-l-(P-D-glucopyranosyloxy)-3,22- dihydroxycholest-5-en-16-yl. It has the formula as follows:

Compound 1

[0020] The term “Compound 2,” or “ip,3p,16p,22S-Tetrahydroxycholest-5-ene 1,16- di-P-D-glucopyranoside,” as used herein, refers to (2R,3R,4S,5S,6R)-2- {[(lR,2S,3aS,3bS,7R,9R,9aR,9bS,l laS)-7-hydroxy-l-[(2S,3S)-3-hydroxy-6-methylheptan-2- yl]-9a,l la-dimethyl-9-{[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxy methyl)oxan-2-yl]oxy}- lH,2H,3H,3aH,3bH,4H,6H,7H,8H,9H,9aH,9bH,10H,HH,l laH-cyclopenta[a]phenanthren-2- yl]oxy]-6-(hydroxymethyl)oxane-3,4,5-triol with CAS number of 168778-13-0. It is also called P-D-Glucopyranoside, (ip,3p,16p,22S)-3,22-dihydroxycholest-5-ene-l,16-diyl bis-, (ip,3p,16p,22S)-3,22-Dihydroxycholest-5-ene-l,16-diyl bis[P-D-glucopyranoside], (22S)- Cholest-5-en-ip,3p,16p,22-tetraol-3,16-di-O-P-D-glucopyranos ide, or (22S)-Cholest-5-ene-

1 P,3 P, 16p,22-tetrol 1 , 16-di-O-P-D-glucopyranoside. It has the formula as follows:

Compound 2

[0021] The term “a sodium -glucose cotransporter-2 inhibitor,” or “SGLT2 inhibitor,” as used herein, refers to a compound or substance which exhibits an inhibitory effect on sodiumsugar carboxy-2 (SGLT2), in particular on human SGLT2. The inhibitory effect on hSGLT2 measured by IC50 is preferably 1,000 nM or less, more preferably 100 nM or less, and most preferably 50 nM or less. The IC50 value of an SGLT2 inhibitor is typically greater than 0.01 nM, or even greater than 0.1 nM. The inhibitory effect on hSGLT2 can be measured by methods known in the literature, in particular as described in application WO 2005/092877 or WO 2007/093610 (page 23/24); is hereby incorporated by reference. The term "SGLT2 inhibitor" also includes the pharmaceutically acceptable salts, hydrates and solvates thereof, including the respective crystal forms.

[0022] In one embodiment, the known SGLT2 inhibitor is selected from the group consisting of dapagliflozin, canagliprofine, empagliflozin, artigliprozine, resmogliflozin, sergliprozine and their derivatives.

[0023] For example, the known SGLT2 inhibitor may include a class of prescription medicines that are FDA-approved for use with diet and exercise to lower blood sugar in adults with type 2 diabetes. The known medicines in the SGLT2 inhibitor class may include canagliflozin, dapagliflozin, and empagliflozin. They are available as single-ingredient products and also in combination with other diabetes medicines such as metformin. SGLT2 inhibitors lower blood sugar by causing the kidneys to remove sugar from the body through the urine.

[0024] Curr Opin Endocrinol Diabetes Obes. 2017 February ; 24(1): 73-79. doi: 10.1097/MED to Hsia et al provides a list of other compounds as the SGLT2 inhibitor.

[0025] However, none of these known SGLT2 inhibitors are natural compounds and they can only be use as a drug and not as a food or supplements.

[0026] In one embodiments, it was found for the first time that hydroxycholest-5-ene glycoside or its derivatives can be used both as a food or supplements and as a sodium-glucose cotransporter-2 (SGLT2) inhibitor to effectively inhibit SGLT2, thus improving metabolic health.

[0027] The term “active ingredient,” as used herein refer to any SGLT2 inhibitor (e.g., hydroxycholest-5-ene glycoside or its derivatives) according to the present invention.

[0028] The term “nutritional composition,” or “nutritional supplement,” as used herein, refers to a nutritional product that provides nutrients to an individual that may otherwise not be consumed in sufficient quantities by the individual. For instance, a nutritional composition or nutritional supplement of the present invention may include vitamins, minerals, fiber, fatty acids, or amino acids. Nutritional compositions or nutritional supplements of the present invention may for example be provided in the form of a pill, a tablet, a lozenge, a chewy capsule or tablet, a tablet or capsule, or a powder supplement that can for example be dissolved in water or sprinkled on food.

[0029] In one embodiment, nutritional compositions or nutritional supplements of the present invention may provide selected nutrients while not representing a significant portion of the overall nutritional needs of a subject. Typically, they do not represent more than 0.1%, 1%, 5%, 10% or 20% of the daily energy need of a subject. A nutritional composition or nutritional supplement of the present invention may be used in any subject, such as a subject during pregnancy, e.g., as a maternal supplement.

[0030] As used herein, an “effective amount,” or “pharmaceutically effective amount,” as used herein, refers to an amount that prevents a deficiency, treats a disease or medical condition in an individual or, more generally, reduces symptoms, manages progression of the diseases or provides a nutritional, physiological, or medical benefit to the individual. The relative terms “promote,” “improve,” “increase,” “enhance” and the like refer to the effects of a composition comprising a hydroxycholest-5-ene glycoside or its derivatives (both as a food or supplement and as a sodium-glucose cotransporter-2 (SGLT2) inhibitor to effectively inhibit SGLT2, thus improving metabolic health) relative to a composition lacking the hydroxycholest-5-ene glycoside or its derivatives, but otherwise identical.

[0031] The term “unit dosage form,” as used herein, refers to physically discrete units suitable as unitary dosages for human and animal subjects, each unit containing a predetermined quantity of the nutritional composition disclosed herein in an amount sufficient to produce the desired effect, preferably in association with a pharmaceutically acceptable diluent, carrier or vehicle. The specifications for the unit dosage form depend on the particular compounds employed, the effect to be achieved, and the pharmacodynamics associated with each compound in the host. In an embodiment, the unit dosage form can be a predetermined amount of powder in a sachet.

[0032] The term “nutritional product,” as used herein, refers to any product that can be used to provide nutrition to a subject. Typically, a nutritional product contains a protein source, a carbohydrate source and a lipid source.

[0033] The term “food product,” as used herein, refers to any kind of product that may be safely consumed by a human or an animal. A food product may be in solid, semi-solid or liquid form and may comprise one or more nutrients, foods or nutritional supplements. For instance, the food product may additionally comprise the following nutrients and micronutrients: a source of proteins, a source of lipids, a source of carbohydrates, vitamins and minerals. The food product may also contain anti-oxidants, stabilizers (when provided in solid form) or emulsifiers (when provided in liquid form).

[0034] The term “functional food product,” as used herein, refers to a food product providing an additional health-promoting or disease-preventing function to the individual.

[0035] The term “healthy ageing product,” as used herein, refers to a product providing an additional health-promoting or disease-preventing function related to healthy ageing to the individual.

[0036] The term “dairy products,” as used herein, refers to food products produced from milk or fractions of milk from animals such as cows, goats, sheep, yaks, horses, camels, and other mammals. Examples of dairy products are low fat milk (e.g., 0.1%, 0.5% or 1.5% fat), fat-free milk, milk powder, whole milk, whole milk products, butter, buttermilk, buttermilk products, skim milk, skim milk products, high milk-fat products, condensed milk, creme fraiche, cheese, ice cream and confectionery products, probiotic drinks or probiotic yoghurt type drinks.

[0037] The term “dairy alternative product,” as used herein, refers to products similar to dairy products but produced without milk.

[0038] The term “milk,” as used herein, is defined by Codex Alimentarius as the normal mammary secretion of milking animals obtained from one or more milkings without either addition to it or extraction from it, intended for consumption as liquid milk or for further processing.

[0039] The term “beverage product,” as used herein, refers to a nutritional product in liquid or semi-liquid form that may be safely consumed by an individual.

[0040] The term “diet product,” as used herein, refers to a food product with a restricted and/or reduced caloric content.

[0041] The term “pet food product,” as used herein, refers to a nutritional product that is intended for consumption by pets. A pet, or companion animal, as referenced herein, is to be understood as an animal selected from dogs, cats, birds, fish, rodents such as mice, rats.

[0042] As used herein, an “effective amount” is an amount that prevents a deficiency, treats a disease or medical condition in an individual or, more generally, reduces symptoms, manages progression of the diseases or provides a nutritional, physiological, or medical benefit to the individual.

[0043] All ingredients of the composition can be admixed together or alternatively the composition can be provided in the form of a kit of parts wherein ingredients or groups of ingredients are provided separately. These separate compositions may be intended to be consumed separately or together.

[0044] The descriptions of simple chains like methyl, pentyl, dodecyl are known to the person skilled in the art. For example, methyl is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms — CH3. Pentyl is a five-carbon alkyl functional group (substituent) with chemical formula -C5H11. Dodecyl is a twelve-carbon alkyl functional group (substituent) with chemical formula -C12H25.

[0045] The term “alkyl,” as used herein, refers to a branched or unbranched saturated hydrocarbon chain having from 1 to 5 carbon atoms.

[0046] As used herein, the term “ring,” refers to any covalently closed structure. A ring may include, for example, carbocycles (e.g., aryls and cycloalkyls), heterocycles (e.g., heteroaryls and non-aromatic heterocycles), aromatics (e.g. aryls and heteroaryls), and non-aromatics (e.g., cycloalkyls and non-aromatic heterocycles). A ring may be optionally substituted. A ring may form part of a ring system.

[0047] As used herein, the term “ring system,” refers to two or more rings. In some embodiments, two or more of the rings may be fused. The term “fused,” as used herein, refers to structures in which two or more rings share one or more bonds.

[0048] The term “halogen,” as used herein, refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

[0049] The term “glycoside,” as used herein, refers to a compound in which at least one sugar is bound to another functional group via a glycosidic bond. Typically, the glycosidic chain can comprise 1 to 4 sugar units.

[0050] The term “glycosidic bond,” as used herein, refers to a bond formed between the hemiacetal or hemiketal group of a sugar and the chemical group of a compound. The chemical group comprising a glycosidic bond can be shown as -OH (O-glycoside), or -CR1R2R3 (C- glycoside).

[0051] The term “glycosylated hydroxybenzoate,” as used herein, refers to a compound in which at least one hydroxyl of the hydroxybenzoate ring is glycosylated.

[0052] The terms “acylglucosylated benzoate,” as used herein, refers to a compound in which at least one hydroxyl of the hydroxybenzoate ring is glucosylated, and at least one hydroxyl of the glucose moiety is esterified by an organic acid. Typical examples or organic acid may comprise acetic, substituted benzoic, cinnamic (caffeic, ferulic, p-coumaric), and/or phenylpropanoic (dihydrocaffeic) acids.

[0053] The terms “sulfated O-glycoside,” or “sulfated C-glycoside,” as used herein, refers to a compound in which at least one hydroxyl of the glycosidic chain is esterified by sulfuric acid.

[0054] Non limiting examples of “hydroxylated and/or methoxylated benzoates” may include: 2-hydroxybenzoate; 2-methoxybenzoate; 3 -hydroxybenzoate; 2,3 -dihydroxybenzoate; 2,5-dihydroxybenzoate; 2,6-dihydroxybenzoate; 3,4-dihydroxybenzoate; 2-hydroxy-6- methoxybenzoate; 3 -hydroxy -4-methoxybenzoate; 4-hydroxy-3 -methoxybenzoate; 2,6- dimethoxybenzoate; 4,4-dimethoxybenzoate; 2,6-dimethoxy-3-hydroxybenzoate; 2, 3 -dihydroxy - 6-methoxybenzoate; 3,6-dihydroxy-2-methoxybenzoate; 2, 6-dihydroxy-3 -methoxybenzoate; 3,4- dihydroxy-2, 6-dimethoxybenzoate; 2,3,6-trihydroxybenzoate, 3,4,5-trihydroxybenzoate; 3,4,5- trimethoxybenzoat and others.

[0055] Non limiting examples of “hydroxylated and/or methoxylated cinnamates” may include: (2Z)-3-phenylprop-2-enoate; (2E)-3-phenylprop-2-enoate; (2Z)-3-(4- hy droxyphenyl)prop-2-enoate; (2E)-3 -(4-hy droxyphenyl)prop-2-enoate; (2Z)-3 -(3,4- dihy droxyphenyl)prop-2-enoate; (2E)-3 -(3 ,4-dihy droxyphenyl)prop-2-enoate; (2Z)-3 -(4- hydroxy-3-methoxyphenyl)prop-2-enoate; (2E)-3-(4-hydroxy-3-methoxyphenyl)prop-2-enoate and others.

[0056] The term “analogue,” as used herein, refers to a compound having a structure similar to that of another one, but differing from it in respect of a certain component. A “derivative” is a compound that can be imagined to arise or is actually be synthesized from a parent compound by replacement of one or more atoms with another atom or group of atoms.

[0057] In one embodiment, the term “analogue,” as used herein, refers to a compound having a structure similar to that of another one, but differing from it in respect of a certain component. The term “derivative,” as used herein, refers to any compound that can be imagined to arise or is actually be synthesized from a parent compound by replacement of one or more atoms with another atom or group of atoms.

[0058] The terms “acylated O-glycoside,” or “acylated C-glycoside,” as used herein, refer to a compound in which at least one hydroxyl of the glycosidic chain is esterified by an organic acid. Typical examples or organic acid may comprise acetic, substituted benzoic, cinnamic (caffeic, ferulic, p-coumaric), and/or phenylpropanoic (dihydrocaffeic) acids.

[0059] The terms “sulfated O-glycoside,” or “sulfated C-glycoside,” as used herein, refers to a compound in which at least one hydroxyl of the glycosidic chain is esterified by sulfuric acid.

[0060] The term “methylene dioxy,” as used herein, refers to functional group with the structural formula R-O-CH2-O-R', connected to the rest of a molecule by two chemical bonds.

[0061] It is understood that according to certain embodiments, the compound of the invention or composition thereof may be a nutraceutical composition, pharmaceutical composition, functional food, functional nutrition product, medical food, medical nutrition product, or a dietary supplement.

[0062] The terms "nutraceutical" combines the words "nutrition" and "pharmaceutical". It is a food or food product that provides health and medical benefits, including the prevention and treatment of a condition, disorder, or disease. A nutraceutical is a product isolated or purified from foods that is generally sold in medicinal forms not usually associated with food. A nutraceutical is demonstrated to have a physiological benefit or provide protection against a condition, disorder, or disease. Such products may range from isolated nutrients, dietary supplements and specific diets to genetically engineered foods, herbal products, and processed foods such as cereals, soups, and beverages.

[0063] The term “nutraceutical,” as used herein, denotes usefulness in both nutritional and pharmaceutical fields of application. Thus, novel nutraceutical compositions can be used as supplements to food and beverages and as pharmaceutical formulations for enteral or parenteral application which may be solid formulations, such as capsules or tablets, or liquid formulations, such as solutions or suspensions.

[0064] The nutraceutical compositions according to the present invention may further contain protective hydrocolloids (such as gums, proteins, modified starches), binders, filmforming agents, encapsulating agents/materials, wall/shell materials, matrix compounds, coatings, emulsifiers, surface active agents, solubilising agents (oils, fats, waxes, lecithins etc.), adsorbents, carriers, fillers, co-compounds, dispersing agents, wetting agents, processing aids (solvents), flowing agents, taste-masking agents, weighting agents, jellifying agents, gel-forming agents, antioxidants and antimicrobials.

[0065] Moreover, a multi-vitamin and mineral supplement may be added to nutraceutical compositions of the invention to obtain an adequate amount of an essential nutrient, which is missing in some diets. The multi-vitamin and mineral supplement may also be useful for disease prevention and protection against nutritional losses and deficiencies due to lifestyle patterns.

[0066] The nutraceutical compositions of the invention may be in any galenic form that is suitable for administering to the body, especially in any form that is conventional for oral administration, e.g. in solid forms such as food or feed, food or feed premix, fortified food or feed, tablets, pills, granules, dragees, capsules and effervescent formulations such as powders and tablets, or in liquid forms, such as solutions, emulsions or suspensions as e.g. beverages, pastes and oily suspensions. The pastes may be incorporated in hard or soft shell capsules, whereby the capsules feature e.g. a matrix of (fish, swine, poultry, cow) gelatine, plant proteins or lignin sulfonate. Examples for other application forms are those for transdermal, parenteral or injectable administration. The dietary and pharmaceutical compositions may be in the form of controlled (delayed) release formulations.

[0067] Beverages encompass non-alcoholic and alcoholic drinks as well as liquid preparations to be added to drinking water and liquid food. Non-alcoholic drinks are e.g. soft drinks, sports drinks, fruit juices, teas and milk-based drinks. Liquid foods are e.g. soups and dairy products. The nutraceutical composition comprising the compound of the invention may be added to a soft drink, an energy bar, or a candy.

[0068] If the nutraceutical composition is a pharmaceutical formulation and the composition further contains pharmaceutically acceptable excipients, diluents or adjuvants then standard techniques may be used for their formulation, as e.g., disclosed in Remington's Pharmaceutical Sciences, 20th edition Williams & Wilkins, PA, USA. For oral administration, tablets and capsules are preferably used which contain a suitable binding agent, e.g., gelatine or polyvinyl pyrrolidone, a suitable filler, e.g. lactose or starch, a suitable lubricant, e.g. magnesium stearate, and optionally further additives.

[0069] The term “functional food,” “functional nutrition product,” “medical food,” or “medical nutrition product,” as used herein, refers to any healthy food claimed to have a healthpromoting or disease-preventing property beyond the basic function of supplying nutrients. The general category of functional foods includes processed food or foods fortified with healthpromoting additives, like "vitamin-enriched" products.

[0070] The terms “food,” “food product” and “food composition” or “diet product” mean a product or composition that is intended for ingestion by an individual such as a human and provides at least one nutrient to the individual. The compositions of the present disclosure, including the many embodiments described herein, can comprise, consist of, or consist essentially of the elements disclosed herein, as well as any additional or optional ingredients, components, or elements described herein or otherwise useful in a diet.

[0071] A dietary supplement, also known as food supplement or nutritional supplement, is a preparation intended to supplement the diet and provide nutrients, such as vitamins, minerals, fibre, fatty acids, or amino acids that may be missing or may not be consumed in sufficient quantities in a person's diet. Some countries define dietary supplements as foods, while in others they are defined as drugs or natural health products. Supplements containing vitamins or dietary minerals are included as a category of food in the Codex Alimentarius, a collection of internationally recognized standards, codes of practice, guidelines and other recommendations relating to foods, food production and food safety. These texts are drawn up by the Codex Alimentarius Commission, an organization that is sponsored by the Food and Agriculture Organization of the United Nations (FAO) and the World Health Organization (WHO).

[0072] Compositions intended for an animal, include food compositions to supply the necessary dietary requirements for an animal, animal treats (e.g., biscuits), and/or dietary supplements. The compositions may be a dry composition (e.g., kibble), semi-moist composition, wet composition, or any mixture thereof. In one embodiment, the composition is a dietary supplement such as a gravy, drinking water, beverage, yogurt, powder, granule, paste, suspension, chew, morsel, treat, snack, pellet, pill, capsule, tablet, or any other suitable delivery form. The dietary supplement can comprise a high concentration of the UFA and NORC, and B vitamins and antioxidants. This permits the supplement to be administered to the animal in small amounts, or in the alternative, can be diluted before administration to an animal. The dietary supplement may require admixing, or can be admixed with water or other diluent prior to administration to the animal.

[0073] “Pet food” or “pet treat compositions” comprise from about 15% to about 50% crude protein. The crude protein material may comprise vegetable proteins such as soybean meal, soy protein concentrate, com gluten meal, wheat gluten, cottonseed, and peanut meal, or animal proteins such as casein, albumin, and meat protein. Examples of meat protein useful herein include pork, lamb, equine, poultry, fish, and mixtures thereof. The compositions may further comprise from about 5% to about 40% fat. The compositions may further comprise a source of carbohydrate. The compositions may comprise from about 15% to about 60% carbohydrate. Examples of such carbohydrates include grains or cereals such as rice, com, milo, sorghum, alfalfa, barley, soybeans, canola, oats, wheat, and mixtures thereof. The compositions may also optionally comprise other materials such as dried whey and other dairy by-products.

[0074] As used herein, the term "diabetes" includes insulin-dependent diabetes mellitus (i.e. IDDM, also known as type 1 diabetes) non-insulin-dependent diabetes mellitus (i.e. NIDDM, also known as type 2 diabetes), and prediabetes. Type 1 diabetes is the result of an absolute deficiency of insulin, the hormone which regulates glucose utilization. Type 2 diabetes often occurs in the face of normal, or even elevated levels of insulin and appears to be the result of the inability of tissues to respond appropriately to insulin. This is termed “insulin resistance”. Most type 2 diabetic patients are also overweight or obese. One of the criteria for diagnosing diabetes is the fasting plasma glucose level. A diabetic subject has a fasting plasma glucose level of greater than or equal to 126 mg/dl. A prediabetic subject is someone suffering from prediabetes. A prediabetic subject is a subject with impaired fasting glucose (a fasting plasma glucose level of greater than or equal to 100 mg/dl and less than 126 mg/dl); or impaired glucose tolerance (a 2- hour plasma glucose level of >140 mg/dl and <200 mg/dl); or insulin resistance, resulting in an increased risk of developing diabetes. Prevention of type 2 diabetes includes treatment of prediabetes.

[0075] As used herein, the term "dyslipidemia" encompasses abnormal levels of any lipid fractions as well as specific lipoprotein abnormalities. For example, it refers to elevation of plasma cholesterol and/or elevation of triglycerides and/or elevation of free fatty acids and/or low high- density lipoprotein (HDL) level and/or high low-density lipoprotein (LDL) level and/or high very low-density lipoprotein (VLDL) level. Dyslipidemia may for example contribute to the development of atherosclerosis and ultimately symptomatic vascular disease including coronary heart disease. Dyslipidemia may or may not be associated with diabetes.

[0076] As used herein, the term “metabolic disorder” encompasses any abnormal chemical and enzymatic reactions disrupting normal metabolism due to environmental and genetic factors (environmental factors include physical activity, nutrition), leading to excessive levels or deficiency of certain substances and dysfunction of energy homeostasis. Non-limiting examples of metabolic disorders include diabetes, dyslipidemia, hypertension, being overweight, obesity, and any combination thereof.

[0077] The term “prevention” or “preventing,” as used herein, refers to reduction of risk and/or severity of a condition, disorder, or disease.

[0078] The term “treatment,” “treating,” “treat,” “attenuate,” or “alleviate,” as used herein, refers to both prophylactic or preventive treatment (that prevent and/or slow the development of a targeted pathologic condition or disorder) and curative, therapeutic or disease-modifying treatment, including therapeutic measures that cure, slow down, lessen symptoms of, and/or halt progression of a diagnosed pathologic condition or disorder, and include treatment of patients at risk of contracting a disease or suspected to have contracted a disease, as well as patients who are ill or have been diagnosed as suffering from a disease or medical condition. The term does not necessarily imply that a subject is treated until total recovery. These terms also refer to the maintenance and/or promotion of health in a subject not suffering from a disease but who may be susceptible to the development of an unhealthy condition. These terms are also intended to include the potentiation or otherwise enhancement of one or more primary prophylactic or therapeutic measure. The terms “treatment,” “treat,” “attenuate” and “alleviate” are further intended to include the dietary management of a disease or condition or the dietary management for prophylaxis or prevention a disease or condition. A treatment can be patient- or doctor-related.

[0079] Obesity, which is an excess of body fat relative to lean body mass, is a chronic disease that is highly prevalent in modern society. It is associated not only with a social stigma, but also with decreased life span and numerous medical problems, including adverse psychological development, coronary artery disease, hypertension, stroke, diabetes, hyperlipidemia, and some cancers, (see, e.g., Nishina, et al., Metab. 43:554-558, 1994; Grundy and Barnett, Dis. Mon. 36:641-731, 1990; Rissanen, et al., British Medical Journal, 301 :835-837, 1990).

[0080] The term “obesity related disorders,” as used herein, refers to those diseases or conditions where excessive body weight or high “body mass index (BMI)” has been implicated in the progression or suppression of the disease or condition. Representative examples of obesity related disorders include, without limitation diabetes, diabetic complications, insulin sensitivity, polycystic ovary disease, hyperglycemia, dyslipidemia, insulin resistance, metabolic syndrome, obesity, body weight gain, inflammatory diseases, diseases of the digestive organs, stenocardia, myocardial infarction, sequelae of stenocardia or myocardial infarction, senile dementia, and cerebrovascular dementia. See, Harrison's Principles of Internal Medicine, 13th Ed., McGraw Hill Companies Inc., New York (1994). Examples, without limitation, of inflammatory conditions include diseases of the digestive organs (such as ulcerative colitis, Crohn's disease, pancreatitis, gastritis, benign tumor of the digestive organs, digestive polyps, hereditary polyposis syndrome, colon cancer, rectal cancer, stomach cancer and ulcerous diseases of the digestive organs), stenocardia, myocardial infarction, sequelae of stenocardia or myocardial infarction, senile dementia, cerebrovascular dementia, immunological diseases and cancer in general.

[0081] The term “subject,” “individual,” or “patient,” as used herein, refers to any animal, including a human, that could benefit from one or more of the compounds, compositions or methods disclosed herein. Generally, the subject is a human or an avian, bovine, canine, equine, feline, hircine, lupine, murine, ovine or porcine animal. The “companion animal,” as used herein, refers to any domesticated animal, and includes, without limitation, cats, dogs, rabbits, guinea pigs, ferrets, hamsters, mice, gerbils, horses, cows, goats, sheep, donkeys, pigs, and the like. Preferably, the subject is a human or a companion animal such as a dog or cat. The term “elderly” in the context of a human means an age from birth of at least 60 years, preferably above 63 years, more preferably above 65 years, and most preferably above 70 years. The term “older adult” in the context of a human means an age from birth of at least 45 years, preferably above 50 years, more preferably above 55 years, and includes elderly subjects. For other animals, an “older adult” has exceeded 50% of the average lifespan for its particular species and/or breed within a species. An animal is considered “elderly” if it has surpassed 66% of the average expected lifespan, preferably if it has surpassed the 75% of the average expected lifespan, more preferably if it has surpassed 80% of the average expected lifespan. An elderly cat or dog has an age from birth of at least about 7 years.

[0082] In one embodiment, the term “subject,” as used herein, refers to a mammal. Mammal includes, but is not limited to, rodents, aquatic mammals, domestic animals such as dogs and cats, farm animals such as sheep, pigs, cows and horses, and humans. In one embodiment, the mammal may be a cat, a dog or a human. The human may be a woman, for example, a woman who is trying to get pregnant, or who is pregnant. In one embodiment of the invention, the subject is a mammal selected from the group consisting of a cat, a dog and, a human. For example, the subject may be an old human.

[0083] The term “empagliflozin,” as used herein, refers to is an antidiabetic medication (sold under the brand name Jardiance among others) used to improve glucose control in people with type 2 diabetes, used to reduce the risk of cardiovascular death in adults with type 2 diabetes and established cardiovascular disease, used to reduce the risk of death and hospitalization in people with heart failure and low ejection fraction, and used to reduce the risk of cardiovascular death and hospitalization for heart failure in adults. It can be prescribed instead of metformin and has benefits over sulfonylureas. It may be used together with other medications such as metformin or insulin. It may not be recommended for type 1 diabetes. Empagliflozin is an inhibitor of the sodium glucose co-transporter-2 (SGLT-2), and works by increasing sugar lost in the urine. The IUPAC name for empagliflozin is (2S,3R,4R,5S,6R)-2-[4-Chloro-3-[[4-[(3S)-oxolan-3- yl]oxyphenyl]methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-tri ol.

[0084] The term “canagliflozin,” as used herein, refers to a medication (sold under the brand name Invokana among others) used to treat type 2 diabetes. It is a third-line medication to be tried after metformin, a first-line medication for type 2 diabetes. It is used together with exercise and diet. It is not recommended in type 1 diabetes. Canagliflozin is a sodium-glucose cotransporter-2 (SGLT2) inhibitor. It works by increasing the amount of glucose lost in the urine. The IUPAC name for canagliflozin is (2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2- ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran- 3,4,5-triol.

[0085] The term “dapagliflozin,” or “Dapa,” as used herein, refers to is a medication (sold under the brand names Farxiga (US) and Forxiga (EU) among others) used to treat type 2 diabetes. It is also used to treat adults with certain kinds of heart failure and chronic kidney disease. Dapagliflozin is a sodium-glucose co-transporter-2 (SGLT-2) inhibitor and works by removing sugar from the body with the urine. The IUPAC name for dapagliflozin is (2S,3R,4R,5S,6R)-2- [4-Chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahy dro-2H-pyran-3,4,5-triol.

[0086] The term “ertugliflozin,” as used herein, refers to a medication (sold under the brand name Steglatro) for the treatment of type 2 diabetes. Ertugliflozin is a sodium/glucose cotransporter 2 (SGLT2) inhibitor and is in the class of drugs known as gliflozins. The IUPAC name for ertugliflozin is (lS,2S,3S,4R,5S)-5-[4-Chloro-3-(4-ethoxybenzyl)phenyl]-l- (hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol.

[0087] The term “aglycone,” “aglycon,” or “genin,” as used herein, refers to the compound remaining after the glycosyl group on a glycoside is replaced by a hydrogen atom. For example, the aglycone of a cardiac glycoside would be a steroid molecule.

[0088] Embodiments

[0089] COMPOUNDS AND COMPOSITIONS

[0090] An aspect of the present disclosure is a compound and a composition comprising such a compound for use as a sodium-glucose cotransporter-2 (SGLT2) inhibitor.

[0091] In one embodiment, the compound and the related composition comprising such a compound can be used both as a food or supplement and as a SGLT2 inhibitor to effectively inhibit SGLT2, thus improving a subject’s metabolic health. Thus, the compound of the present invention can avoid the side effect of the known SGLT2 inhibitors.

[0092] Applicant surprisingly found that administering a subject in need thereof a compound of hydroxycholest-5-ene glycoside or its derivatives or related compositions as a SGLT2 inhibitor can effectively inhibit SGLT2, thus improving metabolic health. Significantly, the compound of hydroxy cholest-5-ene glycoside or its derivatives or related compositions can be used as a food or supplement to a subject to effectively inhibit SGLT2 and to avoid any side effects of the known SGLT2 inhibitors, thus improving metabolic health.

[0093] It was previously reported that the known SGLT2 inhibitors (e.g., canagliflozin, dapagliflozin, empagliflozin and ertugliflozin) have many side effects. For example, genital infections seem to be the most common adverse effect of these known SGLT2 inhibitors. Other side effects may also include mycotic infections, urinary tract infections and osmotic diuresis, risk of diabetic ketoacidosis (DKA), decreased bone mineral density and therefore increased risk of bone fractures, increased risk of lower limb amputation, or an increased risk of Fournier gangrene.

[0094] In one embodiment, the compound of hydroxycholest-5-ene glycoside or its derivatives or related compositions as a SGLT2 inhibitor in the present invention can reduce or remove all these side effects.

[0095] In an aspect, the present disclosure relates to a composition for use in the inhibition of SGLT2 in a subject comprising a compound having the general Formula (I). The subject is a mammal such as a cat, a dog or a human. In one embodiment, the subject is a female human or a male human. In one preferred embodiment, the subject is an old female human or an old male human. [0096] In one embodiment, the compound having the general Formula (I) is a hydroxycholest-5-ene glycoside or its derivatives as a sodium-glucose cotransporter-2 (SGLT2) inhibitor.

[0097] Applicant surprisingly found that the compound having the general Formula (I) (e.g., a hydroxycholest-5-ene glycoside or its derivatives) can be used as an effective SGLT2 inhibitor. Further, Applicant surprisingly found that the compound having the general Formula (I) (e.g., a hydroxycholest-5-ene glycoside or its derivatives) can be used both as an effective SGLT2 inhibitor and as a food or supplement.

[0098] In one embodiment, the compound having the general Formula (I) (e.g., a hydroxycholest-5-ene glycoside or its derivatives) may be used as a direct SGLT2 inhibitor. In one embodiment, because the compound having the general Formula (I) (e.g., a hydroxycholest- 5-ene glycoside or its derivatives) can be used a food or supplement, the compound having the general Formula (I) (e.g., a salicin or its derivatives) has no or reduced side effects of the known SGLT2 inhibitors such as dapagliflozin, canagliprofine, empagliflozin, artigliprozine, resmogliflozin, sergliprozine and their derivatives.

[0099] In one embodiment, the compound having the general Formula (I) is a hydroxycholest-5-ene glycoside or its derivatives.

[00100] In one embodiment, the compound having the general Formula (I) for use in the inhibition of SGLT2, wherein the compound has the general formula (I),

(I),

[00101] wherein

[00102] R1 is O-P-D-glucose; O-glycosylated O-P-D-glucose; sulfated O-P-D-glucose; or O-acylated O-P-D-glucose; and

[00103] R2, R3, R4, R5, R6, R7, R8, R9, RIO, R11, and R12 are each independently H;

OH; O-glycoside; O-glycosylated O-glycoside; sulfated O-glycoside; or O-acylated O-glycoside,

[00104] wherein not more than 2 of the alcoholic substituents R2 to R12 can be oxidized to the corresponding ketone.

[00105] In one embodiment, the compound having the general formula (I) for use both as the food or supplement and as the inhibitor of SGLT2 according to claim 1, wherein:

[00106] R7 is O-P-D-glucose; O-glycosylated O-P-D-glucose; sulfated O-P-D-glucose; or O-acylated O-P-D-glucose; and

[00107] Rl, R2, R3, R4, R5, R6, R8, R9, R10, R11, and R12 are each independently H; OH; O-glycoside; O-glycosylated O-glycoside; sulfated O-glycoside; or O-acylated O-glycoside,

[00108] wherein not more than 2 of the alcoholic substituents Rl to R6 and R8 to R12 can be oxidized to the corresponding ketone.

[00109] In one embodiment, the compound having the general formula (I) for use both as the food or supplement and as the inhibitor of SGLT2 according to claim 1, wherein: [00110] R2 is O-P-D-glucose; O-glycosylated O-P-D-glucose; sulfated O-P-D-glucose; or O-acylated O-P-D-glucose; and

[00111] Rl, R3, R4, R5, R6, R7, R8, R9, RIO, R11, and R12 are each independently H; OH; O-glycoside; O-glycosylated O-glycoside; sulfated O-glycoside; or O-acylated O-glycoside,

[00112] wherein not more than 2 of the alcoholic substituents Rl and R3 to R12 can be oxidized to the corresponding ketone.

[00113] In one embodiment, the compound having the general formula (I) for use both as the food or supplement and as the inhibitor of SGLT2 according to claim 1, wherein:

[00114] Rl is a linear or branched O-glycosidic chain containing minimum 1, and maximum 6 sugar residues, wherein the first sugar engaged in the O-glycosidic bond with the 1- hydroxyl of the steroid ring must be O-P-D-glucose, this first glucose residue can be further O- glycosylated, and the O-glycosidic chain can be further sulfated and/or O-acylated; and

[00115] R2, R3, R4, R5, R6, R7, R8, R9, R10, Rl 1, and R12 are each independently H;

OH; a linear or branched O-glycosidic chain containing minimum 1, and maximum 6 sugar residues, wherein the O-glycosidic chain can be further sulfated and/or O-acylated,

[00116] wherein not more than 2 of the alcoholic substituents R2 to R12 can be oxidized to the corresponding ketone.

[00117] In one embodiment, the compound having the general formula (I) for use both as the food or supplement and as the inhibitor of SGLT2 according to claim 1, wherein:

[00118] R7 is a linear or branched O-glycosidic chain containing minimum 1, and maximum 6 sugar residues, wherein the first sugar engaged in the glycosidic bond with the 16- hydroxyl of the steroid ring must be O-P-D-glucose, this first glucose residue can be further O- glycosylated and the O-glycosidic chain can be further sulfated and/or O-acylated; and

[00119] Rl, R2, R3, R4, R5, R6, R8, R9, R10, Rl 1, and R12 are each independently H; OH; a linear or branched O-glycosidic chain containing minimum 1, and maximum 6 sugar residues, wherein the O-glycosidic chain can be further sulfated and/or O-acylated,

[00120] wherein not more than 2 of the alcoholic substituents Rl to R6 and R8 to R12 can be oxidized to the corresponding ketone.

[00121] In one embodiment, the compound having the general formula (I) for use both as the food or supplement and as the inhibitor of SGLT2 according to claim 1, wherein: [00122] R2 is a linear or branched O-glycosidic chain containing minimum 1, and maximum 6 sugar residues, wherein the first sugar engaged in the glycosidic bond with the 3- hydroxyl of the steroid ring must be O-P-D-glucose, this first glucose residue can be further O- glycosylated and the O-glycosidic chain can be further sulfated and/or O-acylated; and

[00123] Rl, R3, R4, R5, R6, R7, R8, R9, RIO, R11, and R12 are each independently H; OH; a linear or branched O-glycosidic chain containing minimum 1, and maximum 6 sugar residues, wherein the O-glycosidic chain can be further sulfated and/or O-acylated,

[00124] wherein not more than 2 of the alcoholic substituents Rl and R3 to R12 can be oxidized to the corresponding ketone.

[00125] In one embodiment, the compound having the general formula (I) for use both as the food or supplement and as the inhibitor of SGLT2 according to claim 1, wherein:

[00126] Rl is a linear or branched O-glycosidic chain containing minimum 1, and maximum 6 sugar residues, wherein the first sugar engaged in the glycosidic bond with the 1- hydroxyl of the steroid ring must be O-P-D-glucose, this first glucose residue can be further O- glycosylated, the O-glycosidic chain can be further sulfated and/or O-acylated, the further sugar residues must belong to the following list: O-P-D-glucopyranosyl; O-P-D-galactopyranosyl; O-P- D-xylopyranosyl; O-6-deoxy-a-L-mannopyranosyl (O-a-L-rhamnosyl); O-a-L-arabinofuranosyl; O-P-D-glucopyranosiduronyl, wherein the acyl residue may be a linear or branched aliphatic or unsaturated hydrocarbon chain with up to maximum 44 carbon atoms; a hydroxylated and/or methoxylated benzoate; or a hydroxylated and/or methoxylated cinnamate; and

[00127] R2, R3, R4, R5, R6, R7, R8, R9, R10, Rl 1, and R12 are each independently H;

OH; a linear or branched O-glycosidic chain containing minimum 1, and maximum 6 sugar residues, wherein the O-glycosidic chain can be further sulfated and/or O-acylated, the sugar residues must belong to the following list: O-P-D-glucopyranosyl; O-P-D-galactopyranosyl; O-P- D-xylopyranosyl; O-6-deoxy-a-L-mannopyranosyl (O-a-L-rhamnosyl); O-a-L-arabinofuranosyl; O-P-D-glucopyranosiduronyl, wherein the acyl residue may be a linear or branched aliphatic or unsaturated hydrocarbon chain with up to maximum 44 carbon atoms; a hydroxylated and/or methoxylated benzoate; or a hydroxylated and/or methoxylated cinnamate;

[00128] wherein not more than 2 of the alcoholic substituents R2 to R12 can be oxidized to the corresponding ketone. [00129] In one embodiment, the compound having the general formula (I) for use both as the food or supplement and as the inhibitor of SGLT2 according to claim 1, wherein:

[00130] R7 is a linear or branched O-glycosidic chain containing minimum 1, and maximum 6 sugar residues, wherein the first sugar engaged in the glycosidic bond with the 16- hydroxyl of the steroid ring must be O-P-D-glucose, this first glucose residue can be further O- glycosylated, the O-glycosidic chain can be further sulfated and/or O-acylated and the further sugar residues must belong to the following list: O-P-D-glucopyranosyl; O-P-D-galactopyranosyl; O-P-D-xylopyranosyl; O-6-deoxy-a-L-mannopyranosyl (O-a-L-rhamnosyl); O-a-L- arabinofuranosyl; O-P-D-glucopyranosiduronyl, wherein the acyl residue may be a linear or branched aliphatic or unsaturated hydrocarbon chain with up to maximum 44 carbon atoms; a hydroxylated and/or methoxylated benzoate; or a hydroxylated and/or methoxylated cinnamate; and

[00131] Rl, R2, R3, R4, R5, R6, R8, R9, R10, R11, and R12 are each independently H; OH; a linear or branched O-glycosidic chain containing minimum 1, and maximum 6 sugar residues, wherein the O-glycosidic chain can be further sulfated and/or O-acylated, the sugar residues must belong to the following list: O-P-D-glucopyranosyl; O-P-D-galactopyranosyl; O-P- D-xylopyranosyl; O-6-deoxy-a-L-mannopyranosyl (O-a-L-rhamnosyl); O-a-L-arabinofuranosyl; O-P-D-glucopyranosiduronyl, wherein the acyl residue may be a linear or branched aliphatic or unsaturated hydrocarbon chain with up to maximum 44 carbon atoms; a hydroxylated and/or methoxylated benzoate; or a hydroxylated and/or methoxylated cinnamate,

[00132] wherein not more than 2 of the alcoholic substituents Rl to R6 and R8 to R12 can be oxidized to the corresponding ketone.

[00133] In one embodiment, the compound having the general formula (I) for use both as the food or supplement and as the inhibitor of SGLT2 according to claim 1, wherein:

[00134] R2 is a linear or branched O-glycosidic chain containing minimum 1, and maximum 6 sugar residues, wherein the first sugar engaged in the glycosidic bond with the 3- hydroxyl of the steroid ring must be O-P-D-glucose, this first glucose residue can be further O- glycosylated, the O-glycosidic chain can be further sulfated and/or O-acylated and the further sugar residues must belong to the following list: O-P-D-glucopyranosyl; O-P-D-galactopyranosyl; O-P-D-xylopyranosyl; O-6-deoxy-a-L-mannopyranosyl (O-a-L-rhamnosyl); O-a-L- arabinofuranosyl; O-P-D-glucopyranosiduronyl, wherein the acyl residue may be a linear or branched aliphatic or unsaturated hydrocarbon chain with up to maximum 44 carbon atoms; a hydroxylated and/or methoxylated benzoate; or a hydroxylated and/or methoxylated cinnamate; and

[00135] Rl, R3, R4, R5, R6, R7, R8, R9, RIO, R11, and R12 are each independently H; OH; a linear or branched O-glycosidic chain containing minimum 1, and maximum 6 sugar residues, wherein the O-glycosidic chain can be further sulfated and/or O-acylated, the sugar residues must belong to the following list: O-P-D-glucopyranosyl; O-P-D-galactopyranosyl; O-P- D-xylopyranosyl; O-6-deoxy-a-L-mannopyranosyl (O-a-L-rhamnosyl); O-a-L-arabinofuranosyl; O-P-D-glucopyranosiduronyl, the acyl residue may be a linear or branched aliphatic or unsaturated hydrocarbon chain with up to maximum 44 carbon atoms; a hydroxylated and/or methoxylated benzoate; or a hydroxylated and/or methoxylated cinnamate,

[00136] wherein not more than 2 of the alcoholic substituents Rl and R3 to R12 can be oxidized to the corresponding ketone.

[00137] In one embodiment, the compound having the general formula (I) for use both as the food or supplement and as the inhibitor of SGLT2 according to claim 1, wherein:

[00138] the compound is compound 1 of (2R,3R,4S,5R,6R)-2- {[(lR,2S,3aS,3bS,7R,9R,9aR,9bS,l laS)-7-hydroxy-l-[(2S,3S)-3-hydroxy-6-methylheptan-2- yl]-9a,l la-dimethyl-9-{[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxy methyl)oxan-2-yl]oxy}- lH,2H,3H,3aH,3bH,4H,6H,7H,8H,9H,9aH,9bH,10H,l 1H,1 laH-cyclopenta[a]phenanthren-2- yl]oxy]-6-(hydroxymethyl)oxane-3,4,5-triol with CAS number 142735-55-5, which is also called Alloside B, (-)-Alloside B or P-D-Galactopyranoside, (ip,3p,16p,22S)-l-(P-D- glucopyranosyloxy)-3,22-dihydroxycholest-5-en-16-yl.

Compound 1

[00139] In one embodiment, the compound having the general formula (I) for use both as the food and supplement as the inhibitor of SGLT2 according to claim 1, wherein:

[00140] the compound is Compound 2 of (2R,3R,4S,5S,6R)-2- {[(lR,2S,3aS,3bS,7R,9R,9aR,9bS,l laS)-7-hydroxy-l-[(2S,3S)-3-hydroxy-6-methylheptan-2- yl]-9a,l la-dimethyl-9-{[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxy methyl)oxan-2-yl]oxy}- lH,2H,3H,3aH,3bH,4H,6H,7H,8H,9H,9aH,9bH,10H,HH,l laH-cyclopenta[a]phenanthren-2- yl]oxy]-6-(hydroxymethyl)oxane-3,4,5-triol with CAS number of 168778-13-0, which is also called P-D-Glucopyranoside, (ip,3p,16p,22S)-3,22-dihydroxycholest-5-ene-l,16-diyl bis-, (ip,3p,16p,22S)-3,22-Dihydroxycholest-5-ene-l,16-diyl bis[P-D-glucopyranoside], (22S)- Cholest-5-en-ip,3p,16p,22-tetraol-3,16-di-O-P-D-glucopyranos ide, (22S)-Cholest-5-ene- ip,3p,16p,22-tetrol 1,16-di-O-P-D-glucopyranoside, or ip,3p,16p,22S-Tetrahydroxycholest-5- ene 1,16-di-P-D-glucopyranoside.

Compound 2

[00141] In one embodiment, the compound having the general formula (I) for use both as the food and supplement as the inhibitor of SGLT2 according to claim 1, wherein:

[00142] the compound is Compound 3.

Compound 3

[00143] In one embodiment, the compound of the present invention for use both as the food and supplement as the inhibitor of SGLT2 according to claim 1, wherein:

[00144] the compound is Compound 4.

Compound 4

[00145] In one embodiment, the compound having the general formula (I) as disclosed herein (e.g., hydroxy cholest-5-ene glycoside or its derivatives; Compounds 1-3) or Compound 4 or its derivatives are for the use to treat or prevent a condition, disorder, or disease related to type 2 diabetes, and/or obesity in a subject.

[00146] In one embodiment, the compound having the general formula (I) as disclosed herein (e.g., hydroxy cholest-5-ene glycoside or its derivatives; Compounds 1-3) or Compound 4 or its derivatives are for the use to treat or prevent a condition, disorder, or disease related to cardiovascular, weight management, renal, kidney or brain.

[00147] In one embodiment, the compound having the general formula (I) as disclosed herein (e.g., hydroxy cholest-5-ene glycoside or its derivatives; Compounds 1-3) or Compound 4 or its derivatives are used as a SGLT2 inhibitor through either a direct inhibition mechanism or an indirect inhibition mechanism.

[00148] In one embodiment, the compound having the general formula (I) as disclosed herein (e.g., hydroxy cholest-5-ene glycoside or its derivatives; Compounds 1-3) or Compound 4 or its derivatives are used as a SGLT2 inhibitor through a direct inhibition mechanism.

[00149] In one embodiment, the inhibition of SGLT2 by using the compound having the general formula (I) as disclosed herein (e.g., hydroxycholest-5-ene glycoside or its derivatives; Compounds 1-3) or Compound 4 or its derivatives can occur anywhere in the subject.

[00150] In one embodiment, the inhibition of SGLT2 by using the compound having the general formula (I) as disclosed herein (e.g., hydroxycholest-5-ene glycoside or its derivatives; Compounds 1-3) and by using Compound 4 or its derivatives is in muscle and/or kidney tissues.

[00151] In one embodiment, the compound having the general formula (I) as disclosed herein (e.g., hydroxy cholest-5-ene glycoside or its derivatives; Compounds 1-3) or Compound 4 or its derivatives may be obtained from a plant or plant extract. [00152] In one embodiment, the compound having the general formula (I) as disclosed herein (e.g., hydroxy cholest-5-ene glycoside or its derivatives; Compounds 1-3) or Compound 4 or its derivatives are for use in the preparation of a medicament for treating or preventing a condition, disorder, or disease responsive to SGLT2 inhibition.

[00153] In one aspect, the present invention relates to a composition comprising the compound having the general formula (I) as disclosed herein (e.g., hydroxycholest-5-ene glycoside or its derivatives; Compounds 1-3) or Compound 4 or its derivatives.

[00154] In one embodiment, the composition comprises a compound of general formula I as disclosed herein (e.g., hydroxy cholest-5-ene glycoside or its derivatives; Compounds 1-3) or Compound 4 or its derivatives for use in the inhibition of SGLT2.

[00155] For example, the composition comprising a compound of general formula I as disclosed herein (e.g., hydroxy cholest-5-ene glycoside or its derivatives; Compounds 1-3) or Compound 4 or its derivatives can be used both as a food or supplement and as an effective SGLT2 inhibitor.

[00156] Thus, in one embodiment, the composition is a food, beverage, or dietary supplement comprising the compound of general formula I as disclosed herein (e.g., hydroxy cholest-5-ene glycoside or its derivatives; Compounds 1-3) or Compound 4 or its derivatives as one of the ingredients.

[00157] In one embodiment, the compound of general formula (I) in the composition is Compound 1, (2R,3R,4S,5R,6R)-2-{[(lR,2S,3aS,3bS,7R,9R,9aR,9bS,l laS)-7-hydroxy-l-

[(2S,3S)-3-hydroxy-6-methylheptan-2-yl]-9a,l la-dimethyl-9-{[(2R,3R,4S,5S,6R)-3,4,5- trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}- lH,2H,3H,3aH,3bH,4H,6H,7H,8H,9H,9aH,9bH,10H,HH,l laH-cyclopenta[a]phenanthren-2- yl]oxy}-6-(hydroxymethyl)oxane-3,4,5-triol with CAS number 142735-55-5.

[00158] In one embodiment, the compound of general formula (I) in the composition is Compound 2, (2R,3R,4S,5S,6R)-2-{[(lR,2S,3aS,3bS,7R,9R,9aR,9bS,l laS)-7-hydroxy-l-

[(2S,3S)-3-hydroxy-6-methylheptan-2-yl]-9a,l la-dimethyl-9-{[(2R,3R,4S,5S,6R)-3,4,5- trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}- lH,2H,3H,3aH,3bH,4H,6H,7H,8H,9H,9aH,9bH,10H,HH,l laH-cyclopenta[a]phenanthren-2- yl]oxy}-6-(hydroxymethyl)oxane-3,4,5-triol with CAS number of 168778-13-0.

[00159] In one embodiment, the compound of general formula (I) in the composition is Compound 3.

[00160] In one embodiment, the compound in the composition is Compound 4.

[00161] In another aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of the compound of general formula (I) as disclosed herein (e.g., hydroxy cholest-5-ene glycoside or its derivatives; Compounds 1-3) or Compound 4 or its derivatives, or a pharmaceutically acceptable salt or solvate thereof, as active ingredient, and a pharmaceutically acceptable carrier, for use in the inhibition of SGLT2.

[00162] The compound of general formula (I) as disclosed herein (e.g., hydroxycholest- 5-ene glycoside or its derivatives; Compounds 1-3) or Compound 4 or its derivatives of the composition for use in the inhibition of SGLT2 may be administered in accordance with the present invention in any pharmaceutically effective amount. Typically, a pharmaceutically effective amount will depend on the type, age, size, health status, lifestyle and/or genetic heritage of the subject. The pharmaceutically effective amount may be split into several smaller amounts and administered throughout the day so as the total daily intake is the effective amount. A person skilled in the art will be able to propose appropriate amounts of the compound of general formula (I) as disclosed herein (e.g., hydroxycholest-5-ene glycoside or its derivatives; Compounds 1-3) or Compound 4 or its derivatives to be consumed per day.

[00163] In one embodiment, the compound of the general Formula (I) (e.g., hydroxy cholest-5-ene glycoside or its derivatives; Compounds 1-3) or Compound 4 or its derivatives in the present invention may be provided in an amount of between about 0.001 mg and about 100 mg per daily dose, 0.005 mg and about 50 mg per daily dose, about 0.01 mg and about 20 mg per daily dose, about 0.015 mg and about 10 mg per daily dose, between about 0.018 mg and about 9.65 mg per daily dose, between about 0.021 mg and about 9.3 mg per daily dose, between about 0.024 mg and about 8.95 mg per daily dose, between about 0.027 mg and about 8.6 mg per daily dose, between about 0.03 mg and about 8.25 mg per daily dose, between about 0.033 mg and about 7.9 mg per daily dose, between about 0.036 mg and about 7.55 mg per daily dose, between about 0.039 mg and about 7.2 mg per daily dose, between about 0.042 mg and about 6.85 mg per daily dose, between about 0.045 mg and about 6.5 mg per daily dose, between about 0.048 mg and about 6.15 mg per daily dose, between about 0.051 mg and about 5.8 mg per daily dose, between about 0.054 mg and about 5.45 mg per daily dose, between about 0.057 mg and about 5.1 mg per daily dose, between about 0.06 mg and about 4.75 mg per daily dose, between about 0.063 mg and about 4.4 mg per daily dose, between about 0.066 mg and about 4.05 mg per daily dose, between about 0.069 mg and about 3.7 mg per daily dose, between about 0.072 mg and about 3.35 mg per daily dose, between about 0.075 mg and about 3.0 mg per daily dose, between about 0.078 mg and about 2.65 mg per daily dose, between about 0.081 mg and about 2.3 mg per daily dose, between about 0.084 mg and about 1.95 mg per daily dose, between about 0.087 mg and about 1.6 mg per daily dose, between about 0.90 mg and about 1.25 mg per daily dose, between about 0.093 mg and about 1.15 mg per daily dose, between about 0.01 mg and about 1.10 mg per daily dose, between about 0.125 mg and about 1.0 mg per daily dose, between about 0.13 mg and about 0.9 mg per daily dose, between about 0.14 mg and about 0.8 mg per daily dose, between about 0.15 mg and about 0.7 mg per daily dose.

[00164] In one embodiment, the compound of the general Formula (I) (e.g., hydroxy cholest-5-ene glycoside or its derivatives; Compounds 1-3) or Compound 4 or its derivatives in the present invention may be provided in a concentration of between about 0.1 nM and about 100 pM, between about 0.5 nM and about 50 pM, between about 1 nM and about 10 pM, between about 2 nM and about 5 pM, between about 3 nM and about 3 pM, between about 5 nM and about 1 pM, between about 6 nM and about 0.8 pM, between about 8 nM and about 0.5 pM, between about 10 nM and about 0.4 pM, between about 15 nM and about 0.1 pM, between about 20 nM and about 0.09 pM, between about 30 nM and about 0.08 pM, between about 40 nM and about 0.07 pM, between about 50 nM and about 0.06 pM, about 10 nM, about 20 nM, about 30 nM, about 40 nM, about 50 nM, about 60 nM, about 70 nM, about 80 nM, about 90 nM, or about 100 nM.

[00165] In one embodiment, the composition for use in the inhibition of SGLT2 comprising the compound of the general Formula (I) (e.g., hydroxycholest-5-ene glycoside or its derivatives; Compounds 1-3) or Compound 4 or its derivatives in an amount of between about 0.1 mg and about 1 mg per daily dose, preferably between about 0.125 mg and about 0.8 mg per daily dose.

[00166] In one embodiment, the composition for use in the inhibition of SGLT2 comprising the compound of the general Formula (I) (e.g., hydroxycholest-5-ene glycoside or its derivatives; Compounds 1-3) or Compound 4 or its derivatives in a concentration of between about 0.1 nM and about 100 pM, between about 0.5 nM and about 50 pM, between about 1 nM and about 10 pM, between about 2 nM and about 5 pM, between about 3 nM and about 3 pM, between about 5 nM and about 1 pM, between about 6 nM and about 0.8 pM, between about 8 nM and about 0.5 pM, between about 10 nM and about 0.4 pM, between about 15 nM and about 0.1 pM, between about 20 nM and about 0.09 pM, between about 30 nM and about 0.08 pM, between about 40 nM and about 0.07 pM, between about 50 nM and about 0.06 pM, about 10 nM, about 20 nM, about 30 nM, about 40 nM, about 50 nM, about 60 nM, about 70 nM, about 80 nM, about 90 nM, or about 100 nM.

[00167] In another embodiment, the nutritional composition or nutritional supplement comprising the compound of the general Formula (I) (e.g., hydroxycholest-5-ene glycoside or its derivatives; Compounds 1-3) or Compound 4 or its derivatives in an amount of about 0.125 mg per daily dose.

[00168] In another embodiment, the nutritional composition or nutritional supplement comprising the compound of the general Formula (I) (e.g., hydroxycholest-5-ene glycoside or its derivatives; Compounds 1-3) or Compound 4 or its derivatives in an amount of about 0.25 mg per daily dose.

[00169] In another embodiment, the nutritional composition or nutritional supplement comprising the compound of the general Formula (I) (e.g., hydroxycholest-5-ene glycoside or its derivatives; Compounds 1-3) or Compound 4 or its derivatives in an amount of about 0.5 mg per daily dose.

[00170] In another embodiment, the nutritional composition or nutritional supplement comprising the compound of the general Formula (I) (e.g., hydroxycholest-5-ene glycoside or its derivatives; Compounds 1-3) or Compound 4 or its derivatives in an amount of about 0.8 mg per daily dose.

[00171] In another embodiment, the nutritional composition or nutritional supplement comprising the compound of the general Formula (I) (e.g., hydroxycholest-5-ene glycoside or its derivatives; Compounds 1-3) or Compound 4 or its derivatives in a concentration of between about 0.1 nM and about 100 pM, between about 0.5 nM and about 50 pM, between about 1 nM and about 10 pM, between about 2 nM and about 5 pM, between about 3 nM and about 3 pM, between about 5 nM and about 1 pM, between about 6 nM and about 0.8 pM, between about 8 nM and about 0.5 pM, between about 10 nM and about 0.4 pM, between about 15 nM and about 0.1 pM, between about 20 nM and about 0.09 pM, between about 30 nM and about 0.08 pM, between about 40 nM and about 0.07 pM, between about 50 nM and about 0.06 pM, about 10 nM, about 20 nM, about 30 nM, about 40 nM, about 50 nM, about 60 nM, about 70 nM, about 80 nM, about 90 nM, or about 100 nM.

[00172] In one embodiment, the composition comprising the compound of the general Formula (I) (e.g., Compounds 1-3 or their derivatives or analogues thereof) or Compound 4 or its derivatives may be used as a nutritional composition or nutritional supplement. For example, the composition comprising the compound of the general Formula (I) (e.g., Compounds 1-3 or their derivatives or analogues thereof) or Compound 4 or its derivatives might be beneficial to a human subject (such as an old adult or a patient whose metabolic health needs improvements) for inhibiting SGLT2, thus improving his/her metabolic health.

[00173] In one embodiment, the composition comprising the compound of the general Formula (I) (e.g., Compounds 1-3 or their derivatives or analogues thereof) or Compound 4 or its derivatives may be used for daily supplemental or routine administration. For example, the composition comprising the compound of the general Formula (I) (e.g., Compounds 1-3 or their derivatives or analogues thereof) or Compound 4 or its derivatives may be administered to an old adult or a patient whose metabolic health needs improvements. In one embodiment, the composition comprising the compound of the general Formula (I) (e.g., Compounds 1-3 or their derivatives or analogues thereof) or Compound 4 or its derivatives may be administered to a human subject with a metabolic disorder such as obesity, type 2 diabetes, cardiovascular disease or with an obesity related disorder such as diabetic complications, insulin sensitivity, polycystic ovary disease, hyperglycemia, dyslipidemia, insulin resistance, metabolic syndrome, obesity, body weight gain, inflammatory diseases, diseases of the digestive organs, stenocardia, myocardial infarction, sequelae of stenocardia or myocardial infarction, senile dementia, and cerebrovascular dementia.

[00174] In some embodiments, the composition comprising the compound of the general Formula (I) (e.g., Compounds 1-3 or their derivatives or analogues thereof) or Compound 4 or its derivatives may further comprise at least one of an excipient, a diluent, or a carrier. In one embodiment, the composition comprising the compound of the general Formula (I) (e.g., Compounds 1-3 or their derivatives or analogues thereof) or Compound 4 or its derivatives may be dissolved or suspended in a diluent or carrier.

[00175] In some embodiments, the composition comprising the compound of the general Formula (I) (e.g., Compounds 1-3 or their derivatives or analogues thereof) or Compound 4 or its derivatives may further comprise an excipient. An exemplary excipient may be an excipient described in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (1986).

[00176] Non-limiting examples of suitable excipients may include a buffering agent, a preservative, a stabilizer, a binder, a compaction agent, a lubricant, a chelator, a dispersion enhancer, a disintegration agent, a flavoring agent, a sweetener, a coloring agent.

[00177] In some embodiments, an excipient may be a buffering agent. Non-limiting examples of suitable buffering agents may include sodium citrate, magnesium carbonate, magnesium bicarbonate, calcium carbonate, and calcium bicarbonate. As a buffering agent, sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium glucomate, aluminum hydroxide, sodium citrate, sodium tartrate, sodium acetate, sodium carbonate, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, trisodium phosphate, tripotassium phosphate, potassium metaphosphate, magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium silicate, calcium acetate, calcium glycerophosphate, calcium chloride, calcium hydroxide and other calcium salts or combinations thereof can be used in a pharmaceutical composition.

[00178] In some embodiments, an excipient may comprise a preservative. Non-limiting examples of suitable preservatives may include antioxidants, such as alpha-tocopherol and ascorbate, and antimicrobials, such as parabens, chlorobutanol, and phenol. Antioxidants can further include but not limited to EDTA, citric acid, ascorbic acid, butylated hydroxytoluene (BHT), butylated hydroxy anisole (BHA), sodium sulfite, p-amino benzoic acid, glutathione, propyl gallate, cysteine, methionine, ethanol and N- acetyl cysteine. In some instances a preservatives can include validamycin A, TL-3, sodium ortho vanadate, sodium fluoride, N-a- tosyl-Phe-chloromethylketone, N-a-tosyl-Lys-chloromethylketone, aprotinin, phenylmethyl sulfonyl fluoride, diisopropylfluorophosphate, kinase inhibitor, phosphatase inhibitor, caspase inhibitor, granzyme inhibitor, cell adhesion inhibitor, cell division inhibitor, cell cycle inhibitor, lipid signaling inhibitor, protease inhibitor, reducing agent, alkylating agent, antimicrobial agent, oxidase inhibitor, or other inhibitor.

[00179] In one embodiment, the composition comprising the compound of the general Formula (I) (e.g., Compounds 1-3 or their derivatives or analogues thereof) or Compound 4 or its derivatives may further comprise a binder. Non-limiting examples of suitable binders can include starches, pregelatinized starches, gelatin, polyvinylpyrolidone, cellulose, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamides, polyvinyloxoazolidone, polyvinylalcohols, C12-C18 fatty acid alcohol, polyethylene glycol, polyols, saccharides, oligosaccharides, and combinations thereof.

[00180] In one embodiment, the binder may be selected from starches such as potato starch, corn starch, wheat starch; sugars such as sucrose, glucose, dextrose, lactose, maltodextrin; natural and synthetic gums; gelatin; cellulose derivatives such as microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, methyl cellulose, ethyl cellulose; polyvinylpyrrolidone (povidone); polyethylene glycol (PEG); waxes; calcium carbonate; calcium phosphate; alcohols such as sorbitol, xylitol, mannitol and water or a combination thereof.

[00181] In some embodiment, the composition comprising the compound of the general Formula (I) (e.g., Compounds 1-3 or their derivatives or analogues thereof) or Compound 4 or its derivatives may further comprise a lubricant as an excipient. Non-limiting examples of suitable lubricants may include magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oils, sterotex, polyoxyethylene monostearate, talc, polyethyleneglycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, and light mineral oil. The lubricants that can be used in a pharmaceutical composition can be selected from metallic stearates (such as magnesium stearate, calcium stearate, aluminum stearate), fatty acid esters (such as sodium stearyl fumarate), fatty acids (such as stearic acid), fatty alcohols, glyceryl behenate, mineral oil, paraffins, hydrogenated vegetable oils, leucine, polyethylene glycols (PEG), metallic lauryl sulfates (such as sodium lauryl sulfate, magnesium lauryl sulfate), sodium chloride, sodium benzoate, sodium acetate and talc or a combination thereof.

[00182] In some embodiments, the composition comprising the compound of the general Formula (I) (e.g., Compounds 1-3 or their derivatives or analogues thereof) or Compound 4 or its derivatives may further comprise a dispersion enhancer as an excipient. Non-limiting examples of suitable dispersants may include starch, alginic acid, polyvinylpyrrolidones, guar gum, kaolin, bentonite, purified wood cellulose, sodium starch glycolate, isoamorphous silicate, and microcrystalline cellulose as high HLB emulsifier surfactants.

[00183] In some embodiments, the composition comprising the compound of the general Formula (I) (e.g., Compounds 1-3 or their derivatives or analogues thereof) or Compound 4 or its derivatives or analogues thereof may further comprise a disintegrant as an excipient. In some embodiments a disintegrant can be a non-effervescent disintegrant. Non-limiting examples of suitable non-effervescent disintegrants may include starches such as com starch, potato starch, pregelatinized and modified starches thereof, sweeteners, clays, such as bentonite, microcrystalline cellulose, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pecitin, and tragacanth. In some embodiments, a disintegrant may be an effervescent disintegrant. Non-limiting examples of suitable effervescent disintegrants may include sodium bicarbonate in combination with citric acid, and sodium bicarbonate in combination with tartaric acid.

[00184] In some embodiments, an excipient may comprise a flavoring agent. Flavoring agents incorporated into an outer layer can be chosen from synthetic flavor oils and flavoring aromatics; natural oils; extracts from plants, leaves, flowers, and fruits; and combinations thereof. In some embodiments, a flavoring agent may be selected from the group consisting of cinnamon oils; oil of wintergreen; peppermint oils; clover oil; hay oil; anise oil; eucalyptus; vanilla; citrus oil such as lemon oil, orange oil, grape and grapefruit oil; and fruit essences including apple, peach, pear, strawberry, raspberry, cherry, plum, pineapple, and apricot.

[00185] In some embodiment, an excipient may comprise a sweetener. Non-limiting examples of suitable sweeteners may include glucose (corn syrup), dextrose, invert sugar, fructose, and mixtures thereof (when not used as a carrier); saccharin and its various salts such as a sodium salt; dipeptide sweeteners such as aspartame; dihydrochalcone compounds, glycyrrhizin; Stevia Rebaudiana (Stevioside); chloro derivatives of sucrose such as sucralose; and sugar alcohols such as sorbitol, mannitol, sylitol, and the like.

[00186] In some embodiments, the composition comprising the compound of the general Formula (I) (e.g., Compounds 1-3 or their derivatives or analogues thereof) or Compound 4 or its derivatives or analogues thereof may comprise a coloring agent. Non-limiting examples of suitable color agents may include food, drug and cosmetic colors (FD&C), drug and cosmetic colors (D&C), and external drug and cosmetic colors (Ext. D&C). A coloring agent may be used as dyes or their corresponding lakes.

[00187] In some embodiments, the composition comprising the compound of the general Formula (I) (e.g., Compounds 1-3 or their derivatives or analogues thereof) or Compound 4 or its derivatives or analogues thereof may comprise a diluent. Non-limiting examples of diluents can include water, glycerol, methanol, ethanol, and other similar biocompatible diluents. In some embodiments, a diluent may be an aqueous acid such as acetic acid, citric acid, maleic acid, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid, or similar. In some embodiments, a diluent may be used to titrate a pH of a compound to a pH such as physiological pH to produce a salt as described above. In other cases, a diluent may be selected from a group comprising alkaline metal carbonates such as calcium carbonate; alkaline metal phosphates such as calcium phosphate; alkaline metal sulfates such as calcium sulfate; cellulose derivatives such as cellulose, microcrystalline cellulose, cellulose acetate; magnesium oxide, dextrin, fructose, dextrose, glyceryl palmitostearate, lactitol, caoline, lactose, maltose, mannitol, simethicone, sorbitol, starch, pregelatinized starch, talc, xylitol and/or anhydrates, hydrates and/or pharmaceutically acceptable derivatives thereof or combinations thereof

[00188] In some embodiments, the composition comprising the compound of the general Formula (I) (e.g., Compounds 1-3 or their derivatives or analogues thereof) or Compound 4 or its derivatives or analogues thereof may comprise a surfactant. Surfactants may be selected from, but not limited to, polyoxyethylene sorbitan fatty acid esters (polysorbates), sodium lauryl sulfate, sodium stearyl fumarate, polyoxyethylene alkyl ethers, sorbitan fatty acid esters, polyethylene glycols (PEG), polyoxyethylene castor oil derivatives, docusate sodium, quaternary ammonium compounds, amino acids such as L- leucine, sugar esters of fatty acids, glycerides of fatty acids or a combination thereof.

[00189] The composition may be administered by any method appreciated by the skilled artisan. For example, the compound of the general Formula (I) (e.g., Compounds 1-3 or their derivatives or analogues thereof) or Compound 4 or its derivatives or analogues thereof of the invention or composition thereof is preferably administered by oral administration. In some embodiments, the compound of the general Formula (I) (e.g., Compounds 1-3 or their derivatives or analogues thereof) or Compound 4 or its derivatives or analogues thereof of the invention or composition thereof may be administered by intravenous administration, topical administration, parenteral administration, intraperitoneal administration, intramuscular administration, intrathecal administration, intralesional administration, intracranial administration, intranasal administration, intraocular administration, intracardiac administration, intravitreal administration, intraosseous administration, intracerebral administration, intraarterial administration, intraarticular administration, intradermal administration, transdermal administration, transmucosal administration, sublingual administration, enteral administration, sublabial administration, insufflation administration, suppository administration, inhaled administration, or subcutaneous administration.

[00190] In one embodiment, the composition of the invention may have an acute effect that can be seen in less than one month. Additionally or alternatively, the composition can have a long-term effect, and thus various embodiments comprise administration of the composition to the individual (e.g., orally) for a time period of at least one month; preferably at least two months, more preferably at least three, four, five or six months; most preferably for at least one year. During the time period, the composition can be administered to the individual at least one day per week; preferably at least two days per week, more preferably at least three, four, five or six days per week; most preferably seven days per week. The composition can be administered in a single dose per day or in multiple separate doses per day. In one embodiment, a single dose is not less than about lOOmg. In one embodiment, a single dose is not more than about lOOOmg. In one embodiment, a single dose is between about lOOmg and about lOOOmg.

[00191] In one embodiment, the composition comprising the compound of the general Formula (I) (e.g., Compounds 1-3 or their derivatives or analogues thereof) or Compound 4 or its derivatives or analogues thereof may be in a liquid form or in a solid form (e.g., solid dosage forms).

[00192] In some embodiments, solid dosage forms of the composition for oral administration may include capsules, tablets, caplets, pills, troches, lozenges, powders, and granules.

[00193] For example, a capsule may comprise a core material comprising the composition comprising the compound of the general Formula (I) (e.g., Compounds 1-3 or their derivatives or analogues thereof) or Compound 4 or its derivatives or analogues thereof and a shell wall that encapsulates a core material. In some embodiments, a core material may comprise at least one of a solid, a liquid, and an emulsion. In some embodiments, a shell wall material may comprise at least one of a soft gelatin, a hard gelatin, and a polymer. Suitable polymers can include but not limited to: cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose (HPMC), methyl cellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose succinate and carboxymethylcellulose sodium; acrylic acid polymers and copolymers, such as those formed from acrylic acid, methacrylic acid, methyl acrylate, ammonio methylacrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate (e.g., those copolymers sold under the trade name "Eudragit"); vinyl polymers and copolymers such as polyvinyl pyrrolidone, polyvinyl acetate, polyvinylacetate phthalate, vinylacetate crotonic acid copolymer, and ethylene-vinyl acetate copolymers; and shellac (purified lac). In some embodiments, at least one polymer may function as taste-masking agents.

[00194] In some embodiments, tablets, pills, and the like may be compressed, multiply compressed, multiply layered, and/or coated. For example, a coating may be single or multiple. In some embodiments, a coating material (i.e., comprising the composition comprising the compound of the general Formula (I) (e.g., Compounds 1-3 or their derivatives or analogues thereof) or Compound 4 or its derivatives or analogues thereof may comprise at least one of a saccharide, a polysaccharide, and glycoproteins extracted from at least one of a plant, a fungus, and a microbe. Non-limiting examples may include corn starch, wheat starch, potato starch, tapioca starch, cellulose, hemicellulose, dextrans, maltodextrin, cyclodextrins, inulins, pectin, mannans, gum arabic, locust bean gum, mesquite gum, guar gum, gum karaya, gum ghatti, tragacanth gum, funori, carrageenans, agar, alginates, chitosans, or gellan gum. In some embodiments, a coating material may comprise a protein. In some embodiments, a coating material may comprise at least one of a fat and/or an oil. In some embodiments, the at least one of a fat and/or an oil may be high temperature melting. In some embodiments, the at least one of a fat and/or an oil may be hydrogenated or partially hydrogenated. In some embodiments, the at least one of a fat and/or an oil may be derived from a plant. In some embodiments, the at least one of a fat and/or an oil may comprise at least one of glycerides, free fatty acids, and fatty acid esters. In some embodiments, a coating material may comprise at least one edible wax. An edible wax may be derived from animals, insects, or plants. Non-limiting examples can include beeswax, lanolin, bayberry wax, carnauba wax, and rice bran wax. Tablets and pills can additionally be prepared with enteric coatings.

[00195] Liquid formulations of the composition comprising the compound of the general Formula (I) (e.g., Compounds 1-3 or their derivatives or analogues thereof) or Compound 4 or its derivatives or analogues thereof may include a syrup (for example, an oral formulation), an intravenous formulation, an intranasal formulation, an ocular formulation (e.g., for treating an eye infection), an otic formulation (e.g., for treating an ear infection), an ointment, a cream, an aerosol, and the like. In some instances, a combination of various formulations may be administered. In some embodiments, a tablet, pill, and the like can be formulated for an extended release profile. In some embodiments, a composition may be formulated to increase the shelf stability when stored in a closed container under standard ambient conditions.

[00196] Each of the components in the composition of the present invention may be used in any amount that is effective in achieving the objective of the present invention (i.e., increasing breastmilk micronutrient levels of a subject after the subject gives birth). For example, the skilled artisan would be able to determine appropriate dosages depending on age, size and health status of each specific subject, on her lifestyle, as well as on her genetic heritage.

[00197] In one embodiment, the amounts used in the present application are amounts per daily dose. The amount of each component may be used as disclosed or changed (e.g., increased or decreased) depending on age, size and health status of each specific subject, on her lifestyle, as well as on her genetic heritage. In one embodiment, the nutritional composition or nutritional supplement of the present invention may be administered regularly, for example two times a day, daily, every two days or weekly.

[00198] In an aspect, the composition of the present invention may be in any form that is suitable to administer all the ingredients. For example, the composition of the present invention can be in the form of a powdered nutritional composition to be reconstituted in milk or water, a food product, a drink, a nutritional supplement or a nutraceutical.

[00199] When the composition of the present invention is in the form of a powdered nutritional composition to be reconstituted in milk or water, the nutritional composition or nutritional supplement may preferably comprise a protein source, a carbohydrate source and a lipid source, preferably together with lecithin. The composition may also comprise soya lecithin and/or a bulking agent. The protein source may be dried milk or dried skimmed milk. As carbohydrate source sucrose and/or maltodextrin may be used. The lipid source may be vegetable oil. The formulation may also alternatively or additionally contain glucose syrup, milk fat, magnesium citrate, choline salts and esters, prebiotic fibers, and/or ascorbyl palmitate. Flavor compounds, such as cocoa powder or honey, for example, may be added to provide taste variations.

[00200] In another aspect, the composition of the present invention may be a product selected from the group consisting of a nutritional product, a functional food product, a healthy ageing product, a dairy product, a dairy alternative product, a beverage product, a diet product, and a pet food product.

[00201] In one embodiment, he composition comprising the compound of the general Formula (I) (e.g., Compounds 1-3 or their derivatives or analogues thereof) or Compound 4 or its derivatives or analogues thereof may be used for treating or preventing a condition, disorder, or disease related to type 2 diabetes, non-alcoholic fatty liver disease and/or obesity in a subject.

[00202] In one embodiment, the condition may be a metabolic disorder such as obesity, type 2 diabetes, cardiovascular disease or an obesity related disorder such as diabetic complications, insulin sensitivity, polycystic ovary disease, hyperglycemia, dyslipidemia, insulin resistance, metabolic syndrome, obesity, body weight gain, inflammatory diseases, diseases of the digestive organs, stenocardia, myocardial infarction, sequelae of stenocardia or myocardial infarction, senile dementia, and cerebrovascular dementia.

[00203] In another embodiment, the composition comprising the compound of the general Formula (I) (e.g., Compounds 1-3 or their derivatives or analogues thereof) or Compound 4 or its derivatives or analogues thereof may be used for treating or preventing a condition selected from the group consisting of obesity, type 2 diabetes, cardiovascular disease, diabetic complications, insulin sensitivity, polycystic ovary disease, hyperglycemia, dyslipidemia, insulin resistance, metabolic syndrome, obesity, body weight gain, inflammatory diseases, diseases of the digestive organs, stenocardia, myocardial infarction, sequelae of stenocardia or myocardial infarction, senile dementia, and cerebrovascular dementia.

[00204] METHODS

[00205] Another aspect of the present disclosure is a method for improving metabolic health (e.g., treating or preventing a condition, disorder, or disease related to type 2 diabetes, and/or obesity, cardiovascular, weight management, renal, kidney or brain, a metabolic disorder or an obesity related disorder) by inhibiting SGLT2. In one embodiment, the method comprises administering a subject in need thereof a composition comprising the general Formula (I) of the present invention as a SGLT2 inhibitor.

[00206] In one embodiment, the method for improving metabolic health comprises treating or preventing a metabolic disorder. In one embodiment, the metabolic disorder comprises obesity, type 2 diabetes, cardiovascular disease. In one embodiment, the metabolic disorder is selected from the group consisting of obesity, type 2 diabetes, and cardiovascular disease. [00207] In another embodiment, the method for improving metabolic health comprises treating or preventing an obesity related disorder. In one embodiment, the obesity related disorder comprises diabetic complications, insulin sensitivity, polycystic ovary disease, hyperglycemia, dyslipidemia, insulin resistance, metabolic syndrome, obesity, body weight gain, inflammatory diseases, diseases of the digestive organs, stenocardia, myocardial infarction, sequelae of stenocardia or myocardial infarction, senile dementia, and cerebrovascular dementia. In one embodiment, the obesity related disorder is selected from the group consisting of diabetic complications, insulin sensitivity, polycystic ovary disease, hyperglycemia, dyslipidemia, insulin resistance, metabolic syndrome, obesity, body weight gain, inflammatory diseases, diseases of the digestive organs, stenocardia, myocardial infarction, sequelae of stenocardia or myocardial infarction, senile dementia, and cerebrovascular dementia.

[00208] In one embodiment, the present disclosure is a method of treating or preventing a condition selected from the group consisting of obesity, type 2 diabetes, cardiovascular disease, diabetic complications, insulin sensitivity, polycystic ovary disease, hyperglycemia, dyslipidemia, insulin resistance, metabolic syndrome, obesity, body weight gain, inflammatory diseases, diseases of the digestive organs, stenocardia, myocardial infarction, sequelae of stenocardia or myocardial infarction, senile dementia, and cerebrovascular dementia.

[00209] In another embodiment, the present disclosure is a method of treating or preventing a condition, disorder, or disease related to type 2 diabetes, non-alcoholic fatty liver disease and/or obesity in a subject by inhibiting SGLT2.

[00210] As disclosed above, the method comprises administering a subject in need thereof a composition comprising at least one of Compounds 1-4.

[00211] In one embodiment, the method comprises administering a subject in need thereof a composition comprising at least Compound 1.

[00212] In one embodiment, the method comprises administering a subject in need thereof a composition comprising at least Compound 2.

[00213] In one embodiment, the compound of the general Formula (I) is Compound 1 of (2R,3R,4S,5R,6R)-2-{[(lR,2S,3aS,3bS,7R,9R,9aR,9bS,l laS)-7-hydroxy-l-[(2S,3S)-3- hydroxy-6-methylheptan-2-yl]-9a,l la-dimethyl-9-{[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6- (hy droxymethyl)oxan-2-yl] oxy } - lH,2H,3H,3aH,3bH,4H,6H,7H,8H,9H,9aH,9bH,10H,HH,l laH-cyclopenta[a]phenanthren-2- yl]oxy}-6-(hydroxymethyl)oxane-3,4,5-triol, with CAS number of 142735-55-5.

[00214] In one embodiment, the compound of the general Formula (I) is Compound 2 of (2R,3R,4S,5S,6R)-2-{[(lR,2S,3aS,3bS,7R,9R,9aR,9bS,l laS)-7-hydroxy-l-[(2S,3S)-3- hydroxy-6-methylheptan-2-yl]-9a,l la-dimethyl-9-{[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6- (hy droxymethyl)oxan-2-yl] oxy } - lH,2H,3H,3aH,3bH,4H,6H,7H,8H,9H,9aH,9bH,10H,HH,l laH-cyclopenta[a]phenanthren-2- yl]oxy}-6-(hydroxymethyl)oxane-3,4,5-triol with CAS number of 168778-13-0.

[00215] In one embodiment, the compound of the present invention is the compound of general Formula (I) selected from the group of Compounds 1-3 and Compound 4.

[00216] In one embodiment, the method comprises administering a subject in need thereof a composition comprising at least one of the Compounds 1-4 to inhibit SGLT2.

[00217] In one embodiment, the inhibition of SGLT2 is through either a direct inhibition mechanism or an indirect inhibition mechanism.

[00218] In one embodiment, the inhibition of SGLT2 is through a direct inhibition mechanism.

[00219] In one embodiment, the inhibition of SGLT2 occurs at any tissue in the subject related to the condition, disorder, or disease.

[00220] In one embodiment, the inhibition of SGLT2 is in muscle, liver and/or kidney tissues.

[00221] In one embodiment, the compound of the general Formula (I) is obtained from a plant or plant extract.

[00222] In one embodiment, the compound of the general Formula (I) of the present invention can be used to inhibit reabsorption of glucose in the kidney and therefore lower blood sugar.

[00223] In one embodiment, binding of different sugars of the compound of the general Formula (I) of the present invention to the glucose site affects the orientation of the aglycone in the access vestibule. Thus, when the aglycone of the compound of the general Formula (I) of the present invention binds it affects the entire inhibitor. Applicant envisions that these mechanisms together might lead to a synergistic interaction. Therefore, variations in the structure of both the sugar and the aglycone of the compound of the general Formula (I) of the present invention are crucial for the pharmacophore of SGLT inhibitors. [00224] In one embodiment, the compound of the general Formula (I) of the present invention and the related composition can lead to at least 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%,

38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%,

55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%,

72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80% decrease on glucose level in the subject as compared with the control subjects who were not administered with the compound of the general Formula (I) of the present invention and the related composition.

[00225] In one embodiment, the decrease on glucose level by the compound of the general Formula (I) of the present invention and the related composition can be sustained up to 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 36 months, or 48 months.

[00226] In another aspect, the present invention relates to an in vitro method of inhibiting SGLT2. The method comprises contacting a compound of general formula (I) as disclosed herein with SGLT2 and determining inhibition of SGLT2.

[00227] In one embodiment, direct inhibition of SGLT2 may be determined by ability to bind to SGLT2.

[00228] In yet another aspect, the present invention relates to a method of treatment or prevention of a condition, disorder, or disease related to cardiovascular, weight management, renal, kidney, brain, type 2 diabetes, and/or obesity comprising administration of a composition comprising the compound of general formula (I) as disclosed herein.

[00229] EXAMPLES

[00230] Assay Protocol:

[00231] Briefly CHO-K1 cells stably transfected with SGLT1 or SGLT2 were plated at 20000 cells /well in a 384 plate (Black clear bottom Greiner Bio-One #781091) for 24 hours in 50pl of culture medium( RPMI1640 + 5% serum). Prior to the experiment cells were starved for 3 hours by removing culture medium and replacing it by 20 pl of medium without glucose and serum. The experiment was triggered by the addition of 20 pl of assay buffer containing 320 pM of 1NBDG (fluorescent Glucose analogue) in a glucose and serum free medium with or without compounds in 1% DMSO final and incubated at 37°C for 2h. The cells were then washed 3 times using PBS to remove any trace of extracellular 1NBDG. Fluorescence (RFU) corresponding to 1NBDG uptake inside the transfected cells was then measured on a multimode reader (Bioteck synergy neo signal exc 485 nm; em 535 nm). Data were finally normalized: percentage activity was determined using DMSO as maximum uptake signal (100%) and 10 pM of dapagliflozin as minimum signal (0% full uptake inhibition) using the formula : (x-min)/(max-min)*100.

[00232] In these graphs each compounds (e.g., Compounds 1-4; Table 1) has been tested at 6 different concentrations starting at I OpM with 1/3 serial step dilution in duplicate both against SGLT1 and SGLT2 transfected cell lines. In absence of inhibition (DMSO control) the uptake of 1NBDG is maximal resulting in a high RFU signal which is used to determine the 100% normalized activity, at the opposite in presence of 10pM dapagliflozin there is a complete inhibition of the active transport of 1NBDG, the resulting fluorescence observed in this condition gives the 0% normalized activity: the following formulae is applied for normalization:

[00233] Normalized activity (cpd) = (RFU(cpd)- RFU (dapa))/(RFU (DMSO) - RFU(dapa)).

[00234] Table 1 summarizes SGLT1 and SGLT2 inhibition activities of Compounds 1-

4.

[00235] Table 1 : SGLT1 and SGLT2 Inhibition Activities of Compounds 1-4.

[00236] Example 1. SGLT1 and SGLT2 Inhibition Activities of Compound 1.

[00237] As shown in FIG. 1 and Table 1 for Compound 1, the downward direction of both curves represents therefore an increase in the inhibition of SGLT1 and SGLT2 with the increase of the tested concentration of Compound 1.

[00238] We observe that Compound 1 is active on both targets with different IC50s. Compound 1 is much more potent on SGLT2 than on SGLT1. For example, the IC50 for Compound 1 on SGLT2 is about 70nM and the IC50 for Compound 1 on SGLT1 is about 3|1M.

[00239] Example 2. SGLT1 and SGLT2 Inhibition Activities of Compound 2.

[00240] As shown in FIG. 2 and Table 1 for Compound 2, the downward direction of both curves represents therefore an increase in the inhibition of SGLT1 and SGLT2 with the increase of the tested concentration of Compound 2.

[00241] We observe that Compound 2 is active on both targets with different IC50s. For example, Compound 2 is a partial inhibitor at 10|iM on SGLT1, whereas it is a full SGLT2 inhibitor at lOOnM. The estimated IC50 in both cases are showing that Compound 2 is approximatively 31og selective on SGLT2 vs SGLT1. Specifically, the IC50 for Compound 2 on SGLT2 is smaller than 30nM and the IC50 for Compound 2 on SGLT1 is about 7pM.

[00242] Example 3. SGLT1 and SGLT2 Inhibition Activities of Compound 3.

[00243] As shown in FIG. 3 and Table 1 for Compound 3, the downward direction of both curves represents therefore an increase in the inhibition of SGLT1 and SGLT2 with the increase of the tested concentration of Compound 3. [00244] We observe that Compound 3 is active on both targets with different IC50s. Compound 3 is much more potent on SGLT2 than on SGLT1. Specifically, the IC50 for Compound 3 on SGLT2 is about 30nM and the IC50 for Compound 3 on SGLT1 is about 7pM.

[00245] Example 4. SGLT1 and SGLT2 Inhibition Activities of Compound 4.

[00246] As shown in FIG. 4 and Table 1 for Compound 4, the downward direction of both curves represents therefore an increase in the inhibition of SGLT1 and SGLT2 with the increase of the tested concentration of Compound 4.

[00247] We observe that Compound 4 is active on both targets with different IC50s. Compound 4 is much more potent on SGLT2 than on SGLT1. Specifically, the IC50 for Compound 4 on SGLT2 is about 70nM and the IC50 for Compound 4 on SGLT1 is about 10|iM.